Certain substituted amides, method of making, and method of use thereof

ABSTRACT

At least one chemical entity chosen from compounds of Formula 2  
                 
and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof is described herein. Pharmaceutical compositions comprising at least one chemical entity of the invention, together with at least one pharmaceutically acceptable vehicle chosen from carriers adjuvants, and excipients, are described. Methods of treating patients suffering from certain diseases responsive to inhibition of Btk activity and/or B-cell activity are described. Methods for determining the presence of Btk in a sample are described.

This application claims priority to U.S. Application No. 60/660,746,filed Mar. 10, 2005; Application No. 60/724,860, filed Oct. 6, 2005,Application No. 60/677,763, filed May 3, 2005; and Application No.60/682,111, filed May 17, 2005, each of which is incorporated herein byreference.

Provided herein are certain substituted amides and related compounds,compositions comprising such compounds, and methods of their use.

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Bruton's Tyrosine Kinase (Btk) is a member of the Tecfamily of tyrosine kinases, and is a regulator of early B-celldevelopment as well as mature B-cell activation, signaling, andsurvival.

B-cell signaling through the B-cell receptor (BCR) can lead to a widerange of biological outputs, which in turn depend on the developmentalstage of the B-cell. The magnitude and duration of BCR signals must beprecisely regulated. Aberrant BCR-mediated signaling can causedisregulated B-cell activation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium sign upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmunedisease and/or inflammatory disease has been established inBtk-deficient mouse models. For example, in standard murine preclinicalmodels of systemic lupus erythematosus (SLE), Btk deficiency has beenshown to result in a marked amelioration of disease progression.Moreover, Btk deficient mice can also be resistant to developingcollagen-induced arthritis and can be less susceptible toStaphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as Rituxan) developed todeplete B-cells, represent an approach to the treatment of a number ofautoimmune and/or inflammatory diseases. Because of Btk's role in B-cellactivation, inhibitors of Btk can be useful as inhibitors of B-cellmediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown tobe important for the function of these cells. For example, Btkdeficiency in mice is associated with impaired IgE-mediated mast cellactivation (marked diminution of TNF-alpha and other inflammatorycytokine release), and Btk deficiency in humans is associated withgreatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment ofallergic disorders and/or autoimmune and/or inflammatory diseases suchas: SLE, rheumatoid arthritis, multiple vasculitides, idiopathicthrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis,and asthma. In addition, Btk has been reported to play a role inapoptosis; thus, inhibition of Btk activity can be useful for cancer, aswell as the treatment of B-cell lymphoma and leukemia.

Provided is at least one chemical entity comprising a pharmacophorechosen from radicals of Formula 1

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   * represents a point of attachment;-   R₃ is chosen from optionally substituted piperidinyl, tert-butyl and    isopropyl;-   X is chosen from CH and N; and-   R₁ and R₂ are independently chosen from hydrogen, lower alkyl, and    halo, provided that at least one of R₁ and R₂ is not hydrogen.

Also provided is at least one chemical entity comprising a pharmacophorechosen from radicals of Formula 1A

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   * represents a point of attachment;-   R₄₀ is chosen from hydrogen, hydroxy, lower alkyl, sulfonyl, halo,    lower alkoxy, and heteroaryl; and-   R₁ and R₂ are independently chosen from hydrogen, lower alkyl, and    halo, provided that at least one of R₁ and R₂ is not hydrogen.

Also provided is at least one chemical entity chosen from compounds ofFormula 2:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   R is chosen from optionally substituted cycloalkyl, optionally    substituted aryl and optionally substituted heteroaryl;-   M is chosen from a covalent bond and —CH═CH—.-   Q is chosen from    wherein    -   R₁₀ and R₁₁ are independently chosen from hydrogen, C₁-C₆ alkyl,        and C₁-C₆ haloalkyl; and    -   R₁₂, R₁₃, R₁₄, and R₁₅ are each independently chosen from        hydrogen,        -   C₁-C₆ alkyl,        -   C₁-C₆ haloalkyl,        -   phenyl,        -   substituted phenyl chosen from mono-, di-, and            tri-substituted phenyl wherein the substituents are            independently chosen from hydroxy, nitro, cyano, amino,            halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆ alkyloxy)C₁-C₆            alkoxy, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy,            mono-(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and            amino(C₁-C₆ alkyl),        -   heteroaryl, and        -   substituted heteroaryl chosen from mono-, di-, and            tri-substituted heteroaryl wherein the substituents are            independently chosen from hydroxy, nitro, cyano, amino,            halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆ alkyloxy)C₁-C₆            alkoxy, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy,            mono-(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and            amino(C₁-C₆ alkyl); and-   Z is chosen from optionally substituted phenylene and optionally    substituted pyridylidene;-   W is an optionally substituted heteroaryl group other than    imidazo[1,2-A]pyrazine group; and-   D is a hydrogen bond donor other than hydrogen, provided that    the compound of Formula 2 is not    (4-{6-[(4-chloro-benzyl)-methyl-amino]-pyrazin-2-yl}-phenyl)-piperidin-1-yl-methanone.

Provided is a pharmaceutical composition, comprising at least onechemical entity described herein, together with at least onepharmaceutically acceptable vehicle chosen from carriers, adjuvants, andexcipients.

Also provided is a packaged pharmaceutical composition, comprising

a pharmaceutical composition described herein; and

instructions for using the composition to treat a patient suffering froma disease responsive to inhibition of Btk activity.

Also provided is a method for treating a patient having a diseaseresponsive to inhibition of Btk activity, comprising administering tothe patient an effective amount of at least one chemical entitydescribed herein.

Also provided is a method for treating a patient having a disease chosenfrom cancer, autoimmune diseases, inflammatory diseases, acuteinflammatory reactions, and allergic disorders comprising administeringto the patient an effective amount of at least one chemical entitydescribed herein.

Also provided is a method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a patient undergoingchemotherapy with a chemotherapeutic agent an amount of at least onechemical entity described herein, sufficient to increase the sensitivityof cancer cells to the chemotherapeutic agent.

Also provided is a method of reducing medication error and enhancingtherapeutic compliance of a patient being treated for a diseaseresponsive to inhibition of Btk activity, the method comprisingproviding a packaged pharmaceutical preparation described herein whereinthe instructions additionally include contraindication and adversereaction information pertaining to the packaged pharmaceuticalcomposition.

Also provided is a method for inhibiting ATP hydrolysis, the methodcomprising contacting cells expressing Btk with at least one chemicalentity described herein in an amount sufficient to detectably decreasethe level of ATP hydrolysis in vitro.

Also provided is a method for determining the presence of Btk in asample, comprising contacting the sample with at least one chemicalentity described herein under conditions that permit detection of Btkactivity, detecting a level of Btk activity in the sample, and therefromdetermining the presence or absence of Btk in the sample.

Also provided is a method for inhibiting B-cell activity comprisingcontacting cells expressing Btk with at least one chemical entitydescribed herein in an amount sufficient to detectably decrease B-cellactivity in vitro.

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference, for example, to “a”kinase or “the” kinase is inclusive of one or more kinases.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

“Alkyl” encompasses straight chain and branched chain having theindicated number of carbon atoms, usually from 1 to 20 carbon atoms, forexample 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For exampleC₁-C₆alkyl encompasses both straight and branched chain alkyl of from 1to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and thelike. Alkylene is another subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment. Alkylene groupswill usually have from 2 to 20 carbon atoms, for example 2 to 8 carbonatoms, such as from 2 to 6 carbon atoms. For example, C₀ alkyleneindicates a covalent bond and C₁ alkylene is a methylene group. When analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, “butyl” is meant to include n-butyl,sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl andisopropyl. “Lower alkyl” refers to alkyl groups having one to fourcarbons.

“Cycloalkyl” indicates a saturated hydrocarbon ring group, having thespecified number of carbon atoms, usually from 3 to 7 ring carbon atoms.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl as well as bridged and caged saturated ringgroups such as norbornane.

By “alkoxy” is meant an alkyl group of the indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,3-methylpentoxy, and the like. Alkoxy groups will usually have from 1 to6 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refersto alkoxy groups having one to four carbons.

“Mono- and di-alkylcarboxamide” encompasses a group of the formula—(C═O)NR_(a)R_(b) where R_(a) and R_(b) are independently chosen fromhydrogen and alkyl groups of the indicated number of carbon atoms,provided that R_(a) and R_(b) are not both hydrogen.

By “alkylthio” is meant an alkyl group of the indicated number of carbonatoms attached through a sulfur bridge.

“Acyl” refers to the groups (alkyl)-C(O)—; (cycloalkyl)-C(O)—;(aryl)-C(O)—; (heteroaryl)-C(O)—; and (heterocycloalkyl)-C(O)—, whereinthe group is attached to the parent structure through the carbonylfunctionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl are as described herein. Acyl groups have the indicatednumber of carbon atoms, with the carbon of the keto group being includedin the numbered carbon atoms. For example a C₂ acyl group is an acetylgroup having the formula CH₃(C═O)—.

By “alkoxycarbonyl” is meant an ester group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus aC₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbonatoms attached through its oxygen to a carbonyl linker.

By “amino” is meant the group —NH₂.

“Mono- and di-(alkyl)amino” encompasses secondary and tertiary alkylamino groups, wherein the alkyl groups are as defined above and have theindicated number of carbon atoms. The point of attachment of thealkylamino group is on the nitrogen. Examples of mono- and di-alkylaminogroups include ethylamino, dimethylamino, and methyl-propyl-amino.

“Mono- and di-(alkyl)aminoalkyl” encompasses mono- and di-(alkyl)aminoas defined above linked to an alkyl group.

By “amino(alkyl)” is meant an amino group linked to an alkyl grouphaving the indicated number of carbons. Similarly “hydroxyalkyl” is ahydroxy group linked to an alkyl group.

The term “aminocarbonyl” refers to the group —CONR^(b)R^(c), where

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c) taken together with the nitrogen to which they arebound, form an optionally substituted 5- to 7-memberednitrogen-containing heterocycloalkyl which optionally includes 1 or 2additional heteroatoms selected from O, N, and S in the heterocycloalkylring;

where each substituted group is independently substituted with one ormore substituents independently selected from C₁-C₄ alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄alkylphenyl), cyano, nitro, oxo (as a substitutent for heteroaryl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and—NHSO₂(C₁-C₄ haloalkyl).

“Aryl” encompasses:

-   -   5- and 6-membered carbocyclic aromatic rings, for example,        benzene;    -   bicyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, naphthalene, indane, and tetralin;        and    -   tricyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, fluorene.        For example, aryl includes 5- and 6-membered carbocyclic        aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring        containing 1 or more heteroatoms chosen from N, O, and S. For        such fused, bicyclic ring systems wherein only one of the rings        is a carbocyclic aromatic ring, the point of attachment may be        at the carbocyclic aromatic ring or the heterocycloalkyl ring.        Bivalent radicals formed from substituted benzene derivatives        and having the free valences at ring atoms are named as        substituted phenylene radicals. Bivalent radicals derived from        univalent polycyclic hydrocarbon radicals whose names end in        “-yl” by removal of one hydrogen atom from the carbon atom with        the free valence are named by adding “-idene” to the name of the        corresponding univalent radical, e.g., a naphthyl group with two        points of attachment is termed naphthylidene. Aryl, however,        does not encompass or overlap in any way with heteroaryl,        separately defined below. Hence, if one or more carbocyclic        aromatic rings is fused with a heterocycloalkyl aromatic ring,        the resulting ring system is heteroaryl, not aryl, as defined        herein.

The term “aryloxy” refers to the group —O-aryl.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Haloalkyl” indicates alkyl as defined above having the specified numberof carbon atoms, substituted with 1 or more halogen atoms, up to themaximum allowable number of halogen atoms. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Heteroaryl” encompasses:

-   -   5- to 7-membered aromatic, monocyclic rings containing one or        more, for example, from 1 to 4, or in certain embodiments, from        1 to 3, heteroatoms chosen from N, O, and S, with the remaining        ring atoms being carbon; and    -   bicyclic heterocycloalkyl rings containing one or more, for        example, from 1 to 4, or in certain embodiments, from 1 to 3,        heteroatoms chosen from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring.        For example, heteroaryl includes a 5- to 7-membered        heterocycloalkyl, aromatic ring fused to a 5- to 7-membered        cycloalkyl ring. For such fused, bicyclic heteroaryl ring        systems wherein only one of the rings contains one or more        heteroatoms, the point of attachment may be at the        heteroaromatic ring or the cycloalkyl ring. When the total        number of S and O atoms in the heteroaryl group exceeds 1, those        heteroatoms are not adjacent to one another. In certain        embodiments, the total number of S and O atoms in the heteroaryl        group is not more than 2. In certain embodiments, the total        number of S and O atoms in the aromatic heterocycle is not more        than 1. Examples of heteroaryl groups include, but are not        limited to, (as numbered from the linkage position assigned        priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl,        3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl,        2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl,        thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl,        benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl,        indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and        5,6,7,8-tetrahydroisoquinoline. Bivalent radicals derived from        univalent heteroaryl radicals whose names end in “-yl” by        removal of one hydrogen atom from the atom with the free valence        are named by adding “-idene” to the name of the corresponding        univalent radical, e.g., a pyridyl group with two points of        attachment is a pyridylidene. Heteroaryl does not encompass or        overlap with aryl as defined above.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

In the term “heteroarylalkyl,” heteroaryl and alkyl are as definedherein, and the point of attachment is on the alkyl group. This termencompasses, but is not limited to, pyridylmethyl, thiophenylmethyl, and(pyrrolyl)1-ethyl.

By “heterocycloalkyl” is meant a single aliphatic ring, usually with 3to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3heteroatoms independently selected from oxygen, sulfur, and nitrogen, aswell as combinations comprising at least one of the foregoingheteroatoms. Suitable heterocycloalkyl groups include, for example (asnumbered from the linkage position assigned priority 1), 2-pyrrolinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl,4-piperdyl, and 2,5-piperzinyl. Morpholinyl groups are alsocontemplated, including 2-morpholinyl and 3-morpholinyl (numberedwherein the oxygen is assigned priority 1). Substituted heterocycloalkylalso includes ring systems substituted with one or more oxo moieties,such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

“Carbamimidoyl” refers to the group —C(═NH)—NH₂.

“Substituted carbamimidoyl” refers to the group —C(═NR^(e))—NR^(f)R^(g)where R^(e), R^(f), and R^(g) is independently chosen from: hydrogenoptionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocycloalkyl, provided that at least one ofR^(e), R^(f), and R^(g) is not hydrogen and wherein substituted alkyl,cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively toalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is independently chosen from hydrogen and optionally substitutedC₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl,or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “modulation” refers to a change in kinase activity as adirect or indirect response to the presence of compounds of Formula 1,relative to the activity of the kinase in the absence of the compound.The change may be an increase in activity or a decrease in activity, andmay be due to the direct interaction of the compound with the kinase, ordue to the interaction of the compound with one or more other factorsthat in turn affect kinase activity. For example, the presence of thecompound may, for example, increase or decrease kinase activity bydirectly binding to the kinase, by causing (directly or indirectly)another factor to increase or decrease the kinase activity, or by(directly or indirectly) increasing or decreasing the amount of kinasepresent in the cell or organism.

The term “sulfanyl” includes the groups: —S-(optionally substituted(C₁-C₆)alkyl), —S-(optionally substituted aryl), —S-(optionallysubstituted heteroaryl), and —S-(optionally substitutedheterocycloalkyl). Hence, sulfanyl includes the group C₁-C₆alkylsulfanyl.

The term “sulfinyl” includes the groups: —S(O)—H, —S(O)-(optionallysubstituted (C₁-C₆)alkyl), —S(O)-optionally substituted aryl),—S(O)-optionally substituted heteroaryl), —S(O)-(optionally substitutedheterocycloalkyl); and —S(O)-(optionally substituted amino).

The term “sulfonyl” includes the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted (C₁-C₆)alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-optionally substituted heteroaryl), —S(O₂)-(optionallysubstituted heterocycloalkyl), —S(O₂)-(optionally substituted alkoxy),—S(O₂)-optionally substituted aryloxy), —S(O₂)-optionally substitutedheteroaryloxy), —S(O₂)-(optionally substituted heterocyclyloxy); and—S(O₂)-(optionally substituted amino).

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl, unless otherwise expressly defined, refer respectively toalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).

The term “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, referrespectively to alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl wherein one or more (such as up to 5, for example, upto 3) hydrogen atoms are replaced by a substituent independently chosenfrom:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)) wherein“substituted alkyl” refers to alkyl wherein one or more (such as up to5, for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl). In some embodiments, a substituted alkoxy group is“polyalkoxy” or —O-(optionally substituted alkylene)-(optionallysubstituted alkoxy), and includes groups such as —OCH₂CH₂OCH₃, andresidues of glycol ethers such as polyethyleneglycol, and—O(CH₂CH₂O)_(x)CH₃, where x is an integer of 2-20, such as 2-10, and forexample, 2-5. Another substituted alkoxy group is hydroxyalkoxy or—OCH₂(CH₂)_(y)OH, where y is an integer of 1-10, such as 1-4.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality and wherein substituted refers toalkyl wherein one or more (such as up to 5, for example, up to 3)hydrogen atoms are replaced by a substituent independently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).

The term “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(d) where each R^(d) is independently chosen from: hydroxy,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted acyl, aminocarbonyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheterocycloalkyl, alkoxycarbonyl, sulfinyl and sulfonyl, provided thatonly one R^(d) may be hydroxyl, and wherein substituted alkyl,cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively toalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl); and

wherein optionally substituted acyl, aminocarbonyl, alkoxycarbonyl,sulfinyl and sulfonyl are as defined herein.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid. The personskilled in the art is familiar with reaction conditions for carrying outthe N-oxidation.

Compounds of Formula 1 include, but are not limited to, optical isomersof compounds of Formula 1, racemates, and other mixtures thereof. Inthose situations, the single enantiomers or diastereomers, i.e.,optically active forms, can be obtained by asymmetric synthesis or byresolution of the racemates. Resolution of the racemates can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral high-pressure liquid chromatography (HPLC)column. In addition, compounds of Formula 1 include Z- and E-forms (orcis- and trans-forms) of compounds with carbon-carbon double bonds.Where compounds of Formula 1 exists in various tautomeric forms,chemical entities of the present invention include all tautomeric formsof the compound. Compounds of Formula 1 also include crystal formsincluding polymorphs and clathrates.

Chemical entities of the present invention include, but are not limitedto compounds of Formula 1 and all pharmaceutically acceptable formsthereof. Pharmaceutically acceptable forms of the compounds recitedherein include pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, prodrugs, and mixtures thereof. In certainembodiments, the compounds described herein are in the form ofpharmaceutically acceptable salts. Hence, the terms “chemical entity”and “chemical entities” also encompass pharmaceutically acceptablesalts, solvates, chelates, non-covalent complexes, prodrugs, andmixtures.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compound of Formula 1 is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

As noted above, prodrugs also fall within the scope of chemicalentities, for example ester or amide derivatives of the compounds ofFormula 1. The term “prodrugs” includes any compounds that becomecompounds of Formula 1 when administered to a patient, e.g., uponmetabolic processing of the prodrug. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate and like derivativesof functional groups (such as alcohol or amine groups) in the compoundsof Formula 1.

The term “solvate” refers to the chemical entity formed by theinteraction of a solvent and a compound. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

The term “chelate” refers to the chemical entity formed by thecoordination of a compound to a metal ion at two (or more) points.

The term “non-covalent complex” refers to the chemical entity formed bythe interaction of a compound and another molecule wherein a covalentbond is not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry (G. C. Pimentel andA. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R.Taylor and O. Kennard, “Hydrogen Bond Geometry in Organic Crystals”,Accounts of Chemical Research, 17, pp. 320-326 (1984)).

“Hydrogen bond acceptor” refers to a group comprising an oxygen ornitrogen, especially an oxygen or nitrogen that is sp²-hybridized, anether oxygen, or the oxygen of a sulfoxide or N-oxide.

The term “hydrogen bond donor” refers to an oxygen, nitrogen, orheteroaromatic carbon that bears a hydrogen group containing a ringnitrogen or a heteroaryl group containing a ring nitrogen.

The term “pharmacophore” is known in the art, and, as used herein,refers to a molecular moiety capable of exerting a selected biochemicaleffect, e.g., inhibition of an enzyme, such as inhibition of Btk. Aselected pharmacophore can have more than one biochemical effect, e.g.,can be an inhibitor of one receptor (or enzyme) and an antagonist,agonist or partial agonist of a second receptor (or enzyme). Atherapeutic agent can include one or more pharmacophores, which can havethe same or different biochemical activities.

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules.

The term “active agent” is used to indicate a chemical entity which hasbiological activity. In certain embodiments, an “active agent” is acompound having pharmaceutical utility. For example an active agent maybe an anti-cancer therapeutic.

The term “therapeutically effective amount” of a chemical entity of thisinvention means an amount effective, when administered to a human ornon-human patient, to provide a therapeutic benefit such as ameliorationof symptoms, slowing of disease progression, or prevention of diseasee.g., a therapeutically effective amount may be an amount sufficient todecrease the symptoms of a disease responsive to inhibition of Btkactivity. In some embodiments, a therapeutically effective amount is anamount sufficient to reduce cancer symptoms, the symptoms of an allergicdisorder, the symptoms of an autoimmune and/or inflammatory disease, orthe symptoms of an acute inflammatory reaction. In some embodiments atherapeutically effective amount is an amount sufficient to decrease thenumber of detectable cancerous cells in an organism, detectably slow, orstop the growth of a cancerous tumor. In some embodiments, atherapeutically effective amount is an amount sufficient to shrink acancerous tumor. In certain circumstances a patient suffering fromcancer may not present symptoms of being affected. In some embodiments,a therapeutically effective amount of a chemical entity is an amountsufficient to prevent a significant increase or significantly reduce thedetectable level of cancerous cells or cancer markers in the patient'sblood, serum, or tissues. In methods described herein for treatingallergic disorders and/or autoimmune and/or inflammatory diseases and/oracute inflammatory reactions, a therapeutically effective amount mayalso be an amount sufficient, when administered to a patient, todetectably slow progression of the disease, or prevent the patient towhom the chemical entity is given from presenting symptoms of theallergic disorders and/or autoimmune and/or inflammatory disease, and/oracute inflammatory response. In certain methods described herein fortreating allergic disorders and/or autoimmune and/or inflammatorydiseases and/or acute inflammatory reactions, a therapeuticallyeffective amount may also be an amount sufficient to produce adetectable decrease in the amount of a marker protein or cell type inthe patient's blood or serum. For example, in some embodiments atherapeutically effective amount is an amount of a chemical entitydescribed herein sufficient to significantly decrease the activity ofB-cells. In another example, in some embodiments a therapeuticallyeffective amount is an amount of a chemical entity described hereinsufficient to significantly decrease the number of B-cells. In anotherexample, in some embodiments a therapeutically effective amount is anamount of a chemical entity described herein sufficient to decrease thelevel of anti-acetylcholine receptor antibody in a patient's blood withthe disease myasthenia gravis.

The term “inhibition” indicates a significant decrease in the baselineactivity of a biological activity or process. “Inhibition of Btkactivity” refers to a decrease in Btk activity as a direct or indirectresponse to the presence of at least one chemical entity describedherein, relative to the activity of Btk in the absence of the at leastone chemical entity. The decrease in activity may be due to the directinteraction of the compound with Btk, or due to the interaction of thechemical entity(ies) described herein with one or more other factorsthat in turn affect Btk activity. For example, the presence of thechemical entity(ies) may decrease Btk activity by directly binding tothe Btk, by causing (directly or indirectly) another factor to decreaseBtk activity, or by (directly or indirectly) decreasing the amount ofBtk present in the cell or organism.

Inhibition of Btk activity also refers to observable inhibition of Btkactivity in a standard biochemical assay for Btk activity, such as theATP hydrolysis assay described below. In some embodiments, the chemicalentity described herein has an IC₅₀ value less than or equal to 1micromolar. In some embodiments, the chemical entity has an IC₅₀ valueless than or equal to less than 100 nanomolar. In some embodiments, thechemical entity has an IC₅₀ value less than or equal to 10 nanomolar.

“Inhibition of B-cell activity” refers to a decrease in B-cell activityas a direct or indirect response to the presence of at least onechemical entity described herein, relative to the activity of B-cells inthe absence of the at least one chemical entity. The decrease inactivity may be due to the direct interaction of the compound with Btkor with one or more other factors that in turn affect B-cell activity.

Inhibition of B-cell activity also refers to observable inhibition ofCD86 expression in a standard assay such as the assay described below.In some embodiments, the chemical entity described herein has an IC₅₀value less than or equal to 10 micromolar. In some embodiments, thechemical entity has an IC₅₀ value less than or equal to less than 1micromolar. In some embodiments, the chemical entity has an IC₅₀ valueless than or equal to 500 nanomolar.

“B cell activity” also includes activation, redistribution,reorganization, or capping of one or more various B cell membranereceptors, or membrane-bound immunoglobulins, e.g, IgM, IgG, and IgD.Most B cells also have membrane receptors for Fc portion of IgG in theform of either antigen-antibody complexes or aggregated IgG. B cellsalso carry membrane receptors for the activated components ofcomplement, e.g., C3b, C3d, C4, and C1q. These various membranereceptors and membrane-bound immunoglobulins have membrane mobility andcan undergo redistribution and capping that can initiate signaltransduction.

B cell activity also includes the synthesis or production of antibodiesor immunoglobulins. Immunoglobulins are synthesized by the B cell seriesand have common structural features and structural units. Fiveimmunoglobulin classes, i.e., IgG, IgA, IgM, IgD, and IgE, arerecognized on the basis of structural differences of their heavy chainsincluding the amino acid sequence and length of the polypeptide chain.Antibodies to a given antigen may be detected in all or several classesof immunoglobulins or may be restricted to a single class or subclass ofimmunoglobulin. Autoantibodies or autoimmune antibodies may likewisebelong to one or several classes of immunoglobulins. For example,rheumatoid factors (antibodies to IgG) are most often recognized as anIgM immunoglobulin, but can also consist of IgG or IgA.

In addition, B cell activity also is intended to include a series ofevents leading to B cell clonal expansion (proliferation) from precursorB lymphocytes and differentiation into antibody-synthesizing plasmacells which takes place in conjunction with antigen-binding and withcytokine signals from other cells.

“Inhibition of B-cell proliferation” refers to inhibition ofproliferation of abnormal B-cells, such as cancerous B-cells, e.g.lymphoma B-cells and/or inhibition of normal, non-diseased B-cells. Theterm “inhibition of B-cell proliferation” indicates any significantdecrease in the number of B-cells, either in vitro or in vivo. Thus aninhibition of B-cell proliferation in vitro would be any significantdecrease in the number of B-cells in an in vitro sample contacted withat least one chemical entity described herein as compared to a matchedsample not contacted with the chemical entity(ies).

Inhibition of B-cell proliferation also refers to observable inhibitionof B-cell proliferation in a standard thymidine incorporation assay forB-cell proliferation, such as the assay described herein. In someembodiments, the chemical entity has an IC₅₀ value less than or equal to10 micromolar. In some embodiments, the chemical entity has an IC₅₀value less than or equal to less than 1 micromolar. In some embodiments,the chemical entity has an IC₅₀ value less than or equal to 500nanomolar.

An “allergy” or “allergic disorder” refers to acquired hypersensitivityto a substance (allergen). Allergic conditions include eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions.

“Asthma” refers to a disorder of the respiratory system characterized byinflammation, narrowing of the airways and increased reactivity of theairways to inhaled agents. Asthma is frequently, although notexclusively associated with atopic or allergic symptoms.

By “significant” is meant any detectable change that is statisticallysignificant in a standard parametric test of statistical significancesuch as Student's T-test, where p<0.05.

A “disease responsive to inhibition of Btk activity” is a disease inwhich inhibiting Btk kinase provides a therapeutic benefit such as anamelioration of symptoms, decrease in disease progression, prevention ordelay of disease onset, or inhibition of aberrant activity of certaincell-types (monocytes, B-cells, and mast cells).

“Treatment or treating means any treatment of a disease in a patient,including:

-   -   a) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   b) inhibiting the disease;    -   c) slowing or arresting the development of clinical symptoms;        and/or    -   d) relieving the disease, that is, causing the regression of        clinical symptoms.

“Patient” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation or experiment. The methods ofthe invention can be useful in both human therapy and veterinaryapplications. In some embodiments, the patient is a mammal; in someembodiments the patient is human; and in some embodiments the patient ischosen from cats and dogs.

Provided is at least one chemical entity comprising a pharmacophorechosen from radicals of Formula 1

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   * represents a point of attachment;-   R₃ is chosen from optionally substituted piperidinyl, tert-butyl and    isopropyl;-   X is chosen from CH and N; and-   R₁ and R₂ are independently chosen from hydrogen, lower alkyl, and    halo, provided that at least one of R₁ and R₂ is not hydrogen.

In some embodiments, R₁ and R₂ are independently chosen from hydrogen,methyl, and fluoro. In some embodiments, R₁ is chosen from methyl andfluoro and R₂ is hydrogen. In some embodiments, R₂ is chosen from methyland fluoro and R₁ is hydrogen. In some embodiments, R₁ and R₂ areindependently chosen from methyl and fluoro.

In some embodiments, R₃ is chosen from tert-butyl and iso-propyl. Insome embodiments, R₃ is tert-butyl. In some embodiments, R₃ isiso-propyl. In some embodiments, R₃ is piperidinyl substituted with oneor two groups independently chosen from amino, hydroxy, optionallysubstituted lower alkyl, optionally substituted lower alkoxy, andcarbamoyl. In some embodiments, R₃ is piperidinyl optionally substitutedwith one or two groups independently chosen from amino, hydroxy, methyl,ethyl, methoxy, hydroxymethyl, methoxymethoxy, and carbamoyl. In someembodiments, R₃ is piperidin-1-yl optionally substituted with one or twogroups independently chosen from amino, hydroxy, methyl, ethyl, methoxy,hydroxymethyl, methoxymethoxy, and carbamoyl. In some embodiments, R₃ ispiperidin-1-yl. In some embodiments, X is CH. In some embodiments, X isN.

In certain embodiments, the pharmacophore is coupled to another radicalto form a chemical entity capable of inhibition of Btk. The structure ofthat other radical may vary so long as the chemical entity inhibits Btkas described further below.

Also provided is least one chemical entity comprising a pharmacophorechosen from radicals of Formula 1A

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₁ and R₂ are asdescribed above and wherein R₄₀ is chosen from hydrogen, hydroxy, loweralkyl, sulfonyl, halo, lower alkoxy, and heteroaryl.

In certain embodiments, R₄₀ is chosen from hydrogen and lower alkyl.

Provided is at least one chemical entity chosen from compounds ofFormula 2:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   R is chosen from optionally substituted cycloalkyl, optionally    substituted aryl and optionally substituted heteroaryl;-   M is chosen from a covalent bond and CH═CH—.-   Q is chosen from-   wherein    -   R₁₀ and R₁₁ are independently chosen from hydrogen, C₁-C₆ alkyl,        and C₁-C₆ haloalkyl; and    -   R₁₂, R₁₃, R₁₄, and R₁₅ are each independently chosen from        hydrogen,        -   C₁-C₆ alkyl,        -   C₁-C₆ haloalkyl,        -   phenyl,        -   substituted phenyl chosen from mono-, di-, and            tri-substituted phenyl wherein the substituents are            independently chosen from hydroxy, nitro, cyano, amino,            halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆ alkyloxy)C₁-C₆            alkoxy, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy,            mono-(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and            amino(C₁-C₆ alkyl),        -   heteroaryl, and        -   substituted heteroaryl chosen from mono-, di-, and            tri-substituted heteroaryl wherein the substituents are            independently chosen from hydroxy, nitro, cyano, amino,            halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆ alkyloxy)C₁-C₆            alkoxy, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy,            mono-(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and            amino(C₁-C₆ alkyl); and-   Z is chosen from optionally substituted phenylene and optionally    substituted pyridylidene;-   W is an optionally substituted heteroaryl group; and-   D is a hydrogen bond donor, provided that-   W is not an imidazo[1,2-A]pyrazine group;-   D is not hydrogen; and-   the compound of Formula 2 is not    (4-{6-[(4-chloro-benzyl)-methyl-amino]-pyrazin-2-yl}-phenyl)-piperidin-1-yl-methanone.

In certain embodiments, R is chosen from optionally substituted aryl andoptionally substituted heteroaryl.

In certain embodiments, R is chosen from

-   -   phenyl,    -   substituted phenyl chosen from mono-, di-, and tri-substituted        phenyl wherein the substituents are independently chosen from        hydroxy, lower alkyl, sulfanyl, sulfonyl, optionally substituted        amino, lower alkoxy, lower alkyl substituted with one or more        halo, lower alkoxy substituted with one or more halo, lower        alkyl substituted with hydroxy, lower alkyl substituted with        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   pyridyl,    -   substituted pyridyl chosen from mono-, di-, and tri-substituted        pyridyl wherein the substituents are independently chosen from        hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, optionally        substituted piperidinyl, and heteroaryl,    -   pyrimidinyl,    -   substituted pyrimidinyl chosen from mono-, di-, and        tri-substituted pyridyl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   pyrazinyl,    -   substituted pyrazinyl chosen from mono-, di-, and        tri-substituted pyridyl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   pyridazinyl,    -   substituted pyridazinyl chosen from mono-, di-, and        tri-substituted pyridyl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   oxazol-2-yl,    -   substituted oxazol-2-yl 1 chosen from mono-, di-, and        tri-substituted oxazol-2-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   2H-pyrazol-3-yl,    -   substituted 2H-pyrazol-3-yl chosen from mono-, di-, and        tri-substituted 2H-pyrazol-3-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   [1,2,3]thiadiazol-4-yl,    -   substituted [1,2,3]thiadiazol-4-yl chosen from mono-, di-, and        tri-substituted [1,2,3]thiadiazol-4-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   isoxazol-5-yl,    -   substituted isoxazol-5-yl chosen from mono-, di-, and        tri-substituted isoxazol-5-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,    -   substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from        mono-, di-, and tri-substituted        4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   4,5,6,7-tetrahydrobenzofuran-2-yl,    -   substituted 4,5,6,7-tetrahydrobenzofuran-2-yl chosen from mono-,        di-, and tri-substituted 4,5,6,7-tetrahydrobenzofuran-2-yl        wherein the substituents are independently chosen from hydroxy,        lower alkyl, sulfonyl, halo, lower alkoxy, optionally        substituted piperidinyl, and heteroaryl,    -   4,5,6,7-tetrahydro-1H-indol-2-yl,    -   substituted 4,5,6,7-tetrahydro-1H-indol-2-yl chosen from mono-,        di-, and tri-substituted 4,5,6,7-tetrahydro-1H-indol-2-yl        wherein the substituents are independently chosen from hydroxy,        lower alkyl, sulfonyl, halo, lower alkoxy, optionally        substituted piperidinyl, and heteroaryl and wherein the amine        nitrogen of the indole ring is optionally substituted with an        optionally substituted lower alkyl group,    -   1H-indol-2-yl,    -   substituted 1H-indol-2-yl chosen from mono-, di-, and        tri-substituted 1H-indol-2-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and heteroaryl        and wherein the amine nitrogen of the indole ring is optionally        substituted with an optionally substituted lower alkyl group,    -   benzofuran-2-yl,    -   substituted benzofuran-2-yl chosen from mono-, di-, and        tri-substituted benzofuran-2-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   benzo[b]thiophen-2-yl, and    -   substituted benzo[b]thiophen-2-yl chosen from mono-, di-, and        tri-substituted benzo[b]thiophen-2-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, optionally substituted piperidinyl, and        heteroaryl.

In certain embodiments, R is chosen from

-   -   phenyl,    -   substituted phenyl chosen from mono-, di-, and tri-substituted        phenyl wherein the substituents are independently chosen from        hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, optionally        substituted piperidinyl, and heteroaryl,    -   pyridyl,    -   substituted pyridyl chosen from mono-, di-, and tri-substituted        pyridyl wherein the substituents are independently chosen from        hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, optionally        substituted piperidinyl, and heteroaryl,    -   oxazol-2-yl,    -   substituted oxazol-2-yl 1 chosen from mono-, di-, and        tri-substituted oxazol-2-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   2H-pyrazol-3-yl,    -   substituted 2H-pyrazol-3-yl chosen from mono-, di-, and        tri-substituted 2H-pyrazol-3-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   [1,2,3]thiadiazol-4-yl,    -   substituted [1,2,3]thiadiazol-4-yl chosen from mono-, di-, and        tri-substituted [1,2,3]thiadiazol-4-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,    -   substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from        mono-, di-, and tri-substituted        4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, optionally substituted piperidinyl, and        heteroaryl,    -   isoxazol-5-yl, and    -   substituted isoxazol-5-yl chosen from mono-, di-, and        tri-substituted isoxazol-5-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, optionally substituted piperidinyl, and        heteroaryl.

In certain embodiments, R is chosen from

-   -   phenyl,    -   substituted phenyl chosen from mono-, di-, and tri-substituted        phenyl wherein the substituents are independently chosen from        hydroxy, lower alkyl, sulfanyl, sulfonyl, optionally substituted        amino, lower alkoxy, lower alkyl substituted with one or more        halo, lower alkoxy substituted with one or more halo, lower        alkyl substituted with hydroxy, lower alkyl substituted with        lower alkoxy, and heteroaryl,    -   pyridyl,    -   substituted pyridyl chosen from mono-, di-, and tri-substituted        pyridyl wherein the substituents are independently chosen from        hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, and        heteroaryl,    -   pyrimidinyl,    -   substituted pyrimidinyl chosen from mono-, di-, and        tri-substituted pyridyl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   pyrazinyl,    -   substituted pyrazinyl chosen from mono-, di-, and        tri-substituted pyridyl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   pyridazinyl,    -   substituted pyridazinyl chosen from mono-, di-, and        tri-substituted pyridyl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   oxazol-2-yl,    -   substituted oxazol-2-yl 1 chosen from mono-, di-, and        tri-substituted oxazol-2-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   2H-pyrazol-3-yl,    -   substituted 2H-pyrazol-3-yl chosen from mono-, di-, and        tri-substituted 2H-pyrazol-3-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   [1,2,3]thiadiazol-4-yl,    -   substituted [1,2,3]thiadiazol-4-yl chosen from mono-, di-, and        tri-substituted [1,2,3]thiadiazol-4-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, and heteroaryl,    -   isoxazol-5-yl,    -   substituted isoxazol-5-yl chosen from mono-, di-, and        tri-substituted isoxazol-5-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,    -   substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from        mono-, di-, and tri-substituted        4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, and heteroaryl,    -   4,5,6,7-tetrahydrobenzofuran-2-yl,    -   substituted 4,5,6,7-tetrahydrobenzofuran-2-yl chosen from mono-,        di-, and tri-substituted 4,5,6,7-tetrahydrobenzofuran-2-yl        wherein the substituents are independently chosen from hydroxy,        lower alkyl, sulfonyl, halo, lower alkoxy, and heteroaryl,    -   4,5,6,7-tetrahydro-1H-indol-2-yl,    -   substituted 4,5,6,7-tetrahydro-1H-indol-2-yl chosen from mono-,        di-, and tri-substituted 4,5,6,7-tetrahydro-1H-indol-2-yl        wherein the substituents are independently chosen from hydroxy,        lower alkyl, sulfonyl, halo, lower alkoxy, and heteroaryl and        wherein the amine nitrogen of the indole ring is optionally        substituted with an optionally substituted lower alkyl group,    -   1H-indol-2-yl,    -   substituted 1H-indol-2-yl chosen from mono-, di-, and        tri-substituted 1H-indol-2-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl and wherein the amine nitrogen of        the indole ring is optionally substituted with an optionally        substituted lower alkyl group,    -   benzofuran-2-yl,    -   substituted benzofuran-2-yl chosen from mono-, di-, and        tri-substituted benzofuran-2-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   benzo[b]thiophen-2-yl, and    -   substituted benzo[b]thiophen-2-yl chosen from mono-, di-, and        tri-substituted benzo[b]thiophen-2-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, and heteroaryl.

In certain embodiments, R is chosen from

-   -   phenyl,    -   substituted phenyl chosen from mono-, di-, and tri-substituted        phenyl wherein the substituents are independently chosen from        hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, and        heteroaryl,    -   pyridyl,    -   substituted pyridyl chosen from mono-, di-, and tri-substituted        pyridyl wherein the substituents are independently chosen from        hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, and        heteroaryl,    -   oxazol-2-yl,    -   substituted oxazol-2-yl 1 chosen from mono-, di-, and        tri-substituted oxazol-2-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   2H-pyrazol-3-yl,    -   substituted 2H-pyrazol-3-yl chosen from mono-, di-, and        tri-substituted 2H-pyrazol-3-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl,    -   [1,2,3]thiadiazol-4-yl,    -   substituted [1,2,3]thiadiazol-4-yl chosen from mono-, di-, and        tri-substituted [1,2,3]thiadiazol-4-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, and heteroaryl,    -   4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,    -   substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from        mono-, di-, and tri-substituted        4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein the substituents        are independently chosen from hydroxy, lower alkyl, sulfonyl,        halo, lower alkoxy, and heteroaryl,    -   isoxazol-5-yl, and    -   substituted isoxazol-5-yl chosen from mono-, di-, and        tri-substituted isoxazol-5-yl wherein the substituents are        independently chosen from hydroxy, lower alkyl, sulfonyl, halo,        lower alkoxy, and heteroaryl.

In certain embodiments, R is chosen from4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl and substituted4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from mono-, di-, andtri-substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein thesubstituents are independently chosen from hydroxy, lower alkyl,sulfonyl, halo, lower alkoxy, and heteroaryl.

In certain embodiments, R is chosen from4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl and substituted4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from mono-, di-, andtri-substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein thesubstituents is lower alkyl.

In certain embodiments, R is substituted phenyl chosen from mono-, di-,and tri-substituted phenyl wherein the substituents are independentlychosen from hydroxy, lower alkyl, sulfanyl, sulfonyl, optionallysubstituted amino, lower alkoxy, lower alkyl substituted with one ormore halo, lower alkoxy substituted with one or more halo, lower alkylsubstituted with hydroxy, lower alkyl substituted with lower alkoxy, andheteroaryl.

In certain embodiments, R is substituted phenyl chosen from mono-, di-,and tri-substituted phenyl wherein the substituents are independentlychosen from hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, andheteroaryl. In certain embodiments, R is 4-lower alkyl-phenyl-. Incertain embodiments, R is 4-tert-butyl-phenyl.

In certain embodiments, M is a covalent bond. In certain embodiments, Mis —CH═CH—.

In certain embodiments, R₁₂, R₁₃, R₁₄, and R₁₅ are each independentlychosen from hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and phenyl. In someembodiments, R₁₃, R₁₄, and R₁₅ are independently chosen from hydrogenand C₁-C₆ alkyl. In certain embodiments, R₁₃ is chosen from hydrogen andC₁-C₆ alkyl.

In certain embodiments, Z is chosen from ortho-phenylene,meta-phenylene, para-phenylene, ortho-pyridylidene, meta-pyridylidene,and para-pyridylidene, each of which is optionally substituted with agroup chosen from optionally substituted lower alkyl, optionallysubstituted lower alkoxy, halo, and hydroxy. In certain embodiments, Zis chosen from meta-phenylene and meta-phenylene substituted with agroup chosen from optionally substituted lower alkyl, optionallysubstituted lower alkoxy, halo, and hydroxy. In certain embodiments, Zis chosen from meta-phenylene and meta-phenylene substituted with agroup chosen from lower alkyl and halo. In certain embodiments, Z ischosen from meta-phenylene and meta-phenylene substituted with a groupchosen from methyl and halo.

In certain embodiments, W is an optionally substituted heteroaryl groupthat further comprises a hydrogen bond acceptor.

In certain embodiments,

is chosen from

each of which is optionally substituted with one or two groups chosenfrom hydroxy, cyano, halo, optionally substituted lower alkyl, andoptionally substituted lower alkoxy and wherein

-   R₁₆ is chosen from is chosen from hydrogen, cyano, optionally    substituted cycloalkyl, and optionally substituted lower alkyl;-   R₁₇, R₁₈, R₁₉, R₂₁, R₂₂, and R₂₃ are independently chosen from    hydrogen and optionally substituted lower alkyl; and-   R₂₀ is chosen from hydrogen, hydroxy, cyano, halo, optionally    substituted lower alkyl, and optionally substituted lower alkoxy.

In certain embodiments, R₁₇, R₁₈, R₁₉, R₂₁, and R₂₂ are independentlychosen from hydrogen and lower alkyl.

In some embodiments, R₁₆ is chosen from hydrogen, lower alkyl, and loweralkyl substituted with a group chosen from optionally substitutedalkoxy, optionally substituted amino, and optionally substituted acyl.In some embodiments, R₁₆ is chosen from hydrogen and lower alkyl. Insome embodiments, R₁₆ is chosen from hydrogen, methyl, and ethyl. Insome embodiments, R₁₆ is chosen from methyl and ethyl.

In certain embodiments, R₂₁ is chosen from hydrogen and lower alkyl. Incertain embodiments, R₂₁ is chosen from hydrogen and methyl. In certainembodiments, R₂₁ is hydrogen.

In certain embodiments, R₂₂ is chosen from hydrogen and lower alkyl. Incertain embodiments, R₂₂ is chosen from hydrogen and methyl. In certainembodiments, R₂₂ is hydrogen.

In certain embodiments, R₂₀ is hydrogen.

In certain embodiments,

comprises

wherein Y is chosen from N and CR₂₁; andR₁₆, R₂₁, and R₂₂ are independently chosen from hydrogen and optionallysubstituted lower alkyl.

In certain embodiments, D is —NHR₉ wherein R₉ is chosen from optionallysubstituted aryl and optionally substituted heteroaryl.

In certain embodiments, D is —N(H)—B-L-G wherein

-   -   B is chosen from optionally substituted phenylene, optionally        substituted pyridylidene, optionally substituted        2-oxo-1,2-dihydropyridinyl,    -   wherein    -   * indicates the point of attachment to the group -L-G and the        broken bond    -   indicates the point of attachment to the amino group;    -   X₁ is chosen from N and CR₃₁;    -   X₂ is chosen from N and CR₃₁; and    -   X₃ is chosen from N and CR₃₁; and wherein no more than one of        X₁, X₂, and X₃ is N,    -   R₃₀ is chosen from hydrogen, hydroxy, cyano, halo, optionally        substituted lower alkyl, and optionally substituted lower        alkoxy;    -   R₃₁ is chosen from hydrogen, hydroxy, cyano, halo, optionally        substituted lower alkyl, and optionally substituted lower        alkoxy;    -   L is chosen from optionally substituted C₀-C₄alkylene,        —O-optionally substituted C₀-C₄alkylene, —(C₀-C₄alkylene)(SO)—,        —(C₀-C₄alkylene)(SO₂)—; and —(C₀-C₄alkylene)(C═O)—; and    -   G is chosen from hydrogen, halo, hydroxy, alkoxy, nitro,        optionally substituted alkyl, optionally substituted amino,        optionally substituted carbamimidoyl, optionally substituted        heterocycloalkyl, optionally substituted cycloalkyl, optionally        substituted aryl, and optionally substituted heteroaryl.

In certain embodiments, B is chosen from ortho-phenylene,meta-phenylene, para-phenylene, ortho-pyridylidene, meta-pyridylidene,para-pyridylidene,

In certain embodiments, B is chosen from para-phenylene andmeta-phenylene. In certain embodiments, B is meta-phenylene.

In certain embodiments, B is chosen from

In certain embodiments, L is chosen from optionally substitutedC₀-C₄alkylene, —O-optionally substituted C₀-C₄alkylene,—(C₀-C₄alkylene)(SO₂)—; and —(C₀-C₄alkylene)(C═O)—. In certainembodiments, L is chosen from a covalent bond, —(C═O)—, —CH₂—,—CH₂(C═O)—, —SO₂— and —CH(CH₃)(C═O)—. In some embodiments, L is chosenfrom —(C═O)—, —CH₂—, —CH₂(C═O)—, —SO₂— and —CH(CH₃)(C═O)—.

In certain embodiments, G is chosen from hydrogen, hydroxy, C₁-C₆alkoxy,optionally substituted amino, optionally substitutedC₃-C₇heterocycloalkyl, optionally substituted C₃-C₇cycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In certain embodiments, G is chosen from

-   -   hydrogen,    -   hydroxy,    -   —NR₇R₈ wherein R₇ and R₈ are independently chosen from hydrogen,        optionally substituted acyl, and optionally substituted        (C₁-C₆)alkyl; or wherein R₇ and R₈, together with the nitrogen        to which they are bound, form an optionally substituted 5- to        7-membered nitrogen containing heterocycloalkyl which optionally        further includes one or two additional heteroatoms chosen from        N, O, and S;    -   optionally substituted        5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl,    -   lower alkoxy, and    -   1H-tetrazol-5-yl.

In certain embodiments, G is chosen from

-   -   hydrogen,    -   hydroxy,    -   N-methylethanolamino,    -   optionally substituted morpholin-4-yl,    -   optionally substituted piperazin-1-yl, and    -   optionally substituted homopiperazin-1-yl.

In certain embodiments, G is chosen from

-   -   hydrogen,    -   morpholin-4-yl,    -   4-acyl-piperazin-1-yl,    -   4-lower alkyl-piperazin-1-yl,    -   3-oxo-piperazin-1-yl,    -   homopiperazin-1-yl, and    -   4-lower alkyl-homopiperazin-1-yl.

In certain embodiments, L is a covalent bond and G is hydrogen.

Also provided is at least one chemical entity wherein the radical ofFormula I is attached to the

radical found in Formula 2. Accordingly, also provided is at least onechemical entity chosen from compounds of Formula 3:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein W and D are asdescribed for compounds of Formula 2 and wherein R₁, R₂, R₃, and X areas described for radicals of Formula 1.

Also provided is at least one chemical entity chosen from compounds ofFormula 4:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R, Q, Z, B, L, G,R₁₆, R₂₁, and R₂₂ are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 6:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R, Q, R₂₁, R₂₂, R₁₆,B, L, and G are as described above, and wherein

-   R₄ is chosen from hydrogen, optionally substituted lower alkyl,    optionally substituted lower alkoxy, cyano, halo, and hydroxy.

In certain embodiments, R₄ is chosen from hydrogen, optionallysubstituted lower alkyl, optionally substituted lower alkoxy, cyano,halo, and hydroxy. In somer embodiments, R₄ is chosen from hydrogen,optionally substituted lower alkyl (such as lower alkyl substituted withone or more halo), optionally substituted lower alkoxy (such as loweralkoxy substituted with one or more halo), halo, and hydroxy. In someembodiments, R₄ is chosen from methyl, trifluoromethyl, difluoromethyl,methoxy, trifluoromethoxy, difluoromethoxy, and fluoro. In someembodiments, R₄ is methyl.

Also provided is at least one chemical entity chosen from compounds ofFormula 8:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₄, R₁₆, R₂₁, R₂₂, L,and G are as described above; and wherein

-   X is chosen from N and CH;-   U is chosen from N and CR₄₁;-   R₄₁ is chosen from hydrogen, halo, optionally substituted lower    alkyl, optionally substituted lower alkoxy, hydroxy, nitro, cyano,    sulfhydryl, sulfanyl, sulfinyl, sulfonyl, carboxy, aminocarbonyl,    and optionally substituted amino; and-   R₅ is chosen from hydrogen, halo, hydroxy, lower alkyl, sulfonyl,    optionally substituted amino, lower alkoxy, lower alkyl substituted    with one or more halo, cycloalkyl, lower alkoxy substituted with one    or more halo, lower alkyl substituted with hydroxy, optionally    substituted heterocycloalkyl, and optionally substituted heteroaryl.

In certain embodiments X is N. In certain embodiments, X is CH.

In certain embodiments, U is N. In certain embodiments, U is CR₄₁.

In certain embodiments, R₄₁ is chosen from hydrogen, halo, lower alkyl,lower alkoxy, hydroxy, nitro, and amino. In certain embodiments, R₄₁ ishydrogen.

In some embodiments, R₅ is chosen from hydrogen, hydroxy, lower alkyl,sulfonyl, optionally substituted amino, lower alkoxy, lower alkylsubstituted with one or more halo, lower alkoxy substituted with one ormore halo, lower alkyl substituted with hydroxy, optionally substitutedheterocycloalkyl, and optionally substituted heteroaryl. In someembodiments, R₅ is chosen from hydrogen, optionally substitutedpiperidinyl, and lower alkyl. In some embodiments, R₅ is chosen fromhydrogen, optionally substituted piperidinyl, iso-propyl, andtert-butyl. In some embodiments, R₅ is tert-butyl. In some embodiments,R₅ is iso-propyl. In some embodiments, R₅ is piperidinyl substitutedwith one or two groups independently chosen from amino, hydroxy,optionally substituted lower alkyl, optionally substituted lower alkoxy,and carbamoyl. In some embodiments, R₅ is piperidinyl substituted withone or two groups independently chosen from amino, hydroxy, methyl,ethyl, methoxy, hydroxymethyl, methoxymethoxy, and carbamoyl. In someembodiments, R₅ is piperidin-1-yl substituted with one or two groupsindependently chosen from amino, hydroxy, methyl, ethyl, methoxy,hydroxymethyl, methoxymethoxy, and carbamoyl.

Also provided is at least one chemical entity chosen from compounds ofFormula 10:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₂₂, R₁₆,R₂₁, U, and G are as described above; and whereinf is chosen from 0, 1 and 2.

In certain embodiments, f is 0. In certain embodiments, f is 1. Incertain embodiments, f is 2. In certain embodiments, the groupG-C(O)—(CH₂)_(f)— is attached to the 3 position of the ring. In certainembodiments, the group G-C(O)—(CH₂)_(f)— is attached to the 4 positionof the ring.

Also provided is at least one chemical entity chosen from compounds ofFormula 11:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₁,R₂₂, Y, f, U, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 14:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₁,R₂₂, U, f, and G are as described above, and wherein

-   R₇ and R₈ are independently chosen from hydrogen and optionally    substituted (C₁-C₆)alkyl; or R₇ and R₈, together with the nitrogen    to which they are bound, form an optionally substituted 5- to    7-membered nitrogen-containing heterocycloalkyl which optionally    further includes one or two additional heteroatoms chosen from N, O,    and S.

In certain embodiments, R₇ and R₈, together with the nitrogen to whichthey are bound, form a 5- to 7-membered nitrogen-containingheterocycloalkyl chosen from optionally substituted morpholin-4-yl andoptionally substituted piperazin-1-yl ring.

In certain embodiments, R₇ and R₈, together with the nitrogen to whichthey are bound, form a 5- to 7-membered nitrogen-containingheterocycloalkyl chosen from morpholin-4-yl, 4-acyl-piperazin-1-yl, and4-lower alkyl-piperazin-1-yl.

Also provided is at least one chemical entity chosen from compounds ofFormula 16:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₁,R₂₂, X₁, X₂, X₃, L, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 18:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₁,R₂₂, X₁, X₂, X₃, L, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 5:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein M, R, Q, Z, R₁₆, R₂₂,B, L, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 7:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R, Q, R₄, R₁₆, R₂₂,B, L, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 9:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₂,U, L, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 12:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₂,U, f, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 13:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₂,U, f, R₇, and R₈ are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 15:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₂,f, U, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 17:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₂,X₁, X₂, X₃, L, and G are as described above.

Also provided is at least one chemical entity chosen from compounds ofFormula 19:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₅, X, R₄, R₁₆, R₂₂,X₁, X₂, X₃, L, and G are as described above.

Also provided is at least one chemical entity chosen from

-   4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(morpholine-4-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;-   4-{5-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(N-methylethanolamine-2-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyrazin-3-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(morpholine-4-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;-   4-{5-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(N-methylethanolamine-2-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyrazin-3-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid ethyl ester;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{4-methyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-ethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(3-{4-ethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{4-ethyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-ethyl-6-[4-(N-methylethanolamine-2-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{4-ethyl-6-[4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-fluoro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4,5-dimethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-fluoro-benzoic    acid;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(1H-indazol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(1H-indazol-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[3-fluoro-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-methanesulfonylaminocarbonyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{4-methyl-6-[4-(3-aminopropyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-114-thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1l6-thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1H-tetrazol-5-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid ethyl ester;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{4-methyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-ethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(3-{4-ethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{4-ethyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-ethyl-6-[4-(N-methylethanolamine-2-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{4-ethyl-6-[4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-fluoro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4,5-dimethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-fluoro-benzoic    acid;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(1H-indazol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(1H-indazol-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[3-fluoro-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(5-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-methanesulfonylaminocarbonyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{4-methyl-6-[4-(3-aminopropyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-methyl-5-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1H-tetrazol-5-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-4,5-dimethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[3-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N,N-bis-(2-hydroxyethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N,N-bis-(2-hydroxyethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1H-tetrazol-5-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzenesulfinic    acid morpholin-4-yl ester;-   N-{3-[6-(1H-Benzoimidazol-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(2-cyano-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(6-hydroxy-pyridin-3-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-methyl-N-(cyanomethyl)amino    carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(6-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-pyridin-2-yl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(2-methoxyethyl)amino    carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(2-dimethylaminoethyl)amino    carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-oxazol-2-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-6-(4-oxazol-2-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(4-imidazol-1-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[6-(4-imidazol-1-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N,N-bis-(2-methoxyethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-(3-{6-[4-(4-Acetyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[4-(4-Acetyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-4-tert-butyl-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-Bromo-N-(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-(1-Hydroxy-1-methyl-ethyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-thiomorpholin-4-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(4-imidazol-1-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-Bromo-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-fluoro-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(4-oxo-piperidine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxymethyl-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(2-hydroxymethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   5-tert-Butyl-thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-6-(4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N-(2-(2-hydroxy-ethoxy)-ethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[6-(4-imidazol-1-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N-(2,3-dihydroxy-propyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-thiomorpholin-4-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-hydroxymethyl-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(2-hydroxymethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-thiomorpholin-4-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-cyclohexanecarboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-tert-Butyl-N-(3-{4-ethyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-Dimethylamino-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(4-oxo-4H-pyridin-1-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-Isopropyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-(1-Hydroxy-1-methyl-ethyl)-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-pyrrolidin-1-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-ylmethyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1×6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-N-(2-Methoxy-ethyl)-N-methylaminocarbonyl-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2,4-difluoro-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-methoxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-methyl-N-ethylaminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyrrolidine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3-phenyl-acrylamide;-   N-(2-Fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3-(3-fluoro-phenyl)-acrylamide;-   Benzo[b]thiophene-2-carboxylic acid    (2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   Benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   5-Bromo-thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   5-Bromo-thiophene-2-carboxylic acid    (2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   N-(2-Fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-methylsulfanyl-benzamide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-methylsulfanyl-benzamide;-   4-Ethylsulfanyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   Benzofuran-2-carboxylic acid    (2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4,5-Dibromo-thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[6-(1-oxo-1λ⁴-thiomorpholin-4-yl)-pyridin-3-ylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2,6-difluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-Cyclopropyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(3-fluoro-4-thiomorpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[3-fluoro-4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   4-tert-Butyl-N-(3-{6-[4-(4-methoxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-methanesulfonyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-methanesulfonyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-cyclohexanecarboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(ethyl-methyl-amino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(ethyl-methyl-amino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(2-morpholin-4-yl-pyridin-4-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   Benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   N-(3    -{6-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4-tert-Butyl-N-{3-[6-(4-hydroxymethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-piperidin-1-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-pyridin-4-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-fluoro-3-[4-methyl-6-(4-methylaminomethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(3-ethyl-1-methyl-ureidomethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(3-hydroxymethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(3-hydroxy-pyrrolidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-pyridin-3-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-[2-fluoro-3-(6-{4-[(methanesulfonyl-methyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxy-pyridin-3-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   1-(4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-piperidine-4-carboxylic    acid amide;-   4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-N-methyl-benzamide;-   N-(3-{6-[4-(4-Acetyl-[1,4]diazepan-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-ethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   1-(4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-piperidine-3-carboxylic    acid amide;-   1-(4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-pyrrolidine-2-carboxylic    acid amide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(pyridin-4-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamino]-4-ethyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1-oxy-pyridin-3-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1-oxy-pyridin-4-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide-   4-tert-Butyl-N-(3-{6-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-carbamimidoylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{4-cyclopropyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(3-dimethylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(pyridin-4-ylmethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(pyridin-3-ylmethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   6-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1,6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxy-pyridin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(1-ethyl-2-oxo-1,2-dihydro-pyridin-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{4-cyano-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(piperidin-4-yl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(3-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   5,6,7,8-Tetrahydro-naphthalene-2-carboxylic acid    (2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(1-ethyl-piperidin-4-yl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-hydroxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(4-methanesulfonyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   N-{3-[6-(3-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperidin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(3-hydroxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(2-pyridin-4-yl-ethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-methyl-thiazol-4-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   6-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   N-(2-Methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;-   6-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-nicotinamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(3-amino-phenyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-(3-{6-[4-(4-Amino-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1-ethyl-piperidin-4-yloxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   N-{3-[6-(Benzothiazol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   N-(3-{6-[4-(2-Amino-pyridin-4-ylmethoxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4-tert-Butyl-N-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-{3-[6-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-morpholin-4-yl-acetyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;-   N-(2-Fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   4-tert-Butyl-N-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   6-tert-Butyl-N-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-nicotinamide;-   N-{3-[6-(3-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-6-tert-butyl-nicotinamide;-   3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   N-{3-[6-(2-Amino-pyridin-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N,N-bis-(2-methoxy-ethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-Iodo-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-{3-[6-(3-Benzylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(tetrahydro-pyran-4-yl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-pyrrolidin-1-yl-benzamide;-   Tetrahydro-furan-2-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   4-tert-Butyl-N-(3-{6-[3-(cyclohexanecarbonyl-amino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   N-{3-[6-(3-Amino-4-fluoro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   5,6-Dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[1-(2-morpholin-4-yl-ethyl)-2-oxo-1,2-dihydro-pyridin-4-ylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-(2-Methyl-3-{4-methyl-6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   6-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   6-tert-Butyl-N-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-nicotinamide;-   4-(6-{3-[(6-tert-Butyl-pyridine-3-carbonyl)-amino]-2-methyl-phenyl}-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic    acid;-   Benzo[b]thiophene-5-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[3-(pyridin-3-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[3-(pyridin-3-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   4,4-Dimethyl-chroman-7-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   6-tert-Butyl-N-(3-{6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   6-tert-Butyl-N-(2-fluoro-3-{6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[3-(pyridin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[3-(pyridin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   6-tert-Butyl-N-(3-{6-[4-(2-hydroxymethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   6-tert-Butyl-N-(2-fluoro-3-{6-[4-(2-hydroxymethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   6-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   6-tert-Butyl-N-(3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   6-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   N-{3-[6-(4-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   N-(3-{6-[4-(4-Amino-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-6-tert-butyl-nicotinamide;-   4-(6-{3-[(6-tert-Butyl-pyridine-3-carbonyl)-amino]-2-fluoro-phenyl}-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic    acid;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-3-ylmethoxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-3-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-3-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   6-tert-Butyl-N-[2-fluoro-3-(6-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl]-nicotinamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(hydroxy)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-{3-[6-(3-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-piperidin-1-yl-benzamide;-   6-tert-Butyl-N-[3-(6-{4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-nicotinamide;-   6-tert-Butyl-N-(3-{6-[4-(cyanomethyl-methyl-carbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   N-(3-{6-[4-(4-Ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   6-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   N-{2-Methyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-4-piperidin-1-yl-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(N-(1-amino-ethylidene))-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(3-cyclopropylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(3-piperidin-1-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-[3-(6-{3-[(cyanomethyl-methyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   1-(3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzyl)-piperidine-4-carboxylic    acid amide;-   4-tert-Butyl-N-{3-[6-(3-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-[3-(6-{3-[(2-hydroxy-ethylamino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-(3-{6-[3-(4-hydroxy-piperidin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[3-(2-hydroxymethyl-morpholin-4-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   Tetrahydro-furan-2-carboxylic acid    (4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   Tetrahydro-furan-3-carboxylic acid    (4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   3,4,5,6-Tetrahydro-2H-[1,3′]bipyridinyl-6′-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   6-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   N-(3-{6-[4-(1,1-Dioxo-1l6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;-   6-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1l6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-nicotinamide;-   2-tert-Butyl-pyrimidine-5-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-3-ylmethoxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   N-(3-{6-[4-(4-Amino-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-6-tert-butyl-nicotinamide;-   6-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   5-tert-Butyl-pyrazine-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   6-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   N-(2-Methyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;-   N-(3-{6-[4-(4-Ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;-   6-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;-   6-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-nicotinamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(4-oxo-piperidin-1-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-(3-{6-[4-(3-Amino-propylcarbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-6-tert-butyl-nicotinamide;-   N-(3-{6-[4-(4-Hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide-   6-tert-Butyl-N-(3-{6-[4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   4-Azepan-1-yl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (2-fluoro-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   N-{3-[5-(3-Amino-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   Tetrahydro-furan-2-carboxylic acid    (3-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-phenyl)-amide;-   4-tert-Butyl-N-{3-[1,4-dimethyl-5-(4-morpholin-4-yl-phenylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{5-[4-(1,1-dioxo-1l6-thiomorpholin-4-yl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide;-   6-tert-Butyl-N-(3-{6-[4-(carbamoylmethyl-methyl-carbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   6-tert-Butyl-N-{3-[6-(4-hydroxycarbamoyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-nicotinamide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-(3-{6-[4-(4-Amino-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4-{6-[3-(4-(1-piperidinyl)-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzohydroxamic    acid;-   5-tert-Butyl-pyridine-2-carboxylic acid    (3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   5-tert-Butyl-pyrazine-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-(4-methyl-piperidin-1-yl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (3-{6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-(2-Methyl-3-{4-methyl-5-oxo-6-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;-   4-(1-Piperidinyl)-N-(3-{4-methyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1H-pyrazol-3-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   N-(3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-isonicotinamide;-   5-tert-Butyl-pyrazine-2-carboxylic acid    (3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   Tetrahydro-furan-2-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-fluoro-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (3-{6-[4-(carbamoylmethyl-methyl-carbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[4-(carbamoylmethyl-methyl-carbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-(3-methyl-piperidin-1-yl)-benzamide;-   N-{3-[6-(3-Acetylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   Tetrahydro-furan-3-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   Thiazole-4-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   (3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-carbamic    acid ethyl ester;-   4-tert-Butyl-N-(3-{6-[3-(2-methoxy-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   5-tert-Butyl-pyrimidine-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-(Isopropyl-methyl-amino)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   N-[2-Methyl-3-(4-methyl-5-oxo-6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-4-piperidin-1-yl-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   N-[3-(6-{4-[4-(2-Hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-piperidin-1-yl-benzamide;-   1-(4-{4-Methyl-6-[2-methyl-3-(4-piperidin-1-yl-benzoylamino)-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-piperidine-4-carboxylic    acid amide;-   5-tert-Butyl-pyrazine-2-carboxylic acid    (3-{6-[4-(4-amino-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide;-   4-tert-Butyl-N-[2-fluoro-3-(4-methyl-6-{3-[2-(4-methyl-piperazin-1-yl)-acetylamino]-phenylamino}-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide;-   N-{3-[6-(3-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-fluoro-phenyl}-4-tert-butyl-benzamide;-   N-{3-[6-(3-Amino-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   5-tert-Butyl-pyridine-2-carboxylic acid    (2-methyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   Tetrahydro-furan-2-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   Tetrahydro-furan-2-carboxylic acid    [3-(6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-phenyl]-amide;-   Tetrahydro-furan-2-carboxylic acid    (5-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-fluoro-phenyl)-amide;-   Acetic acid    3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl    ester;-   N-(2-Methyl-3-{6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholin-2-ylmethoxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   6-tert-Butyl-pyridazine-3-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-Imidazol-1-yl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[3-(3-methoxy-propionylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   Furan-2-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   6-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;-   4-tert-Butyl-N-[3-(6-{4-[2-(4-ethyl-piperazin-1-yl)-ethoxy]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   (3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-carbamic    acid tetrahydro-furan-3-yl ester;-   Tetrahydro-furan-2-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   Tetrahydro-furan-2-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   N-{3-[6-(5-Amino-pyridin-3-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-{3-[6-(1H-indol-5-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   Pyrrolidine-2-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   4-tert-Butyl-N-(3-{6-[3-(2-hydroxy-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-[3-(6-cyclopropylamino-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-[3-(6-hydroxy-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-(3-{6-[3-(2-ethoxy-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   N-{3-[6-(3-Amino-4-methyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[3-(2-hydroxy-2-methyl-propionylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   Tetrahydro-pyran-4-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-thiomorpholin-4-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-(4-Hydroxy-piperidin-1-yl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-{3-[6-(3-Amino-4-chloro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-(2-methyl-piperidin-1-yl)-benzamide;-   4,5,6,7-Tetrahydro-benzo[b)]thiophene-2-carboxylic acid    (3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   4-tert-Butyl-N-{3-[6-(3-dimethylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperidin-4-ylmethoxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-[3-(6-{4-[(2-hydroxy-ethyl    amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   (3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-carbamic    acid phenyl ester;-   4-tert-Butyl-N-{3-[6-(4-cyclopropylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-[3-(6-{4-[(carbamoylmethyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-(4-Methoxymethoxy-piperidin-1-yl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-(3-{6-[3-(2-Amino-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   Azetidine-2-carboxylic acid    (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;-   Tetrahydro-furan-2-carboxylic acid    (5-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methyl-phenyl)-amide;-   4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-4-methyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   1-Methyl-3-[4-(morpholine-4-carbonyl)-phenylamino]-5-(2-phenyl-benzooxazol-7-yl)-1H-pyrazin-2-one;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(1-methyl-piperidin-2-ylmethoxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   5-[2-(4-Methoxy-phenyl)-benzooxazol-7-yl]-1-methyl-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazin-2-one;-   4-tert-Butyl-N-{3-[6-(1H-indol-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   N-{3-[6-(3-Aminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(1-ethyl-piperidin-4-ylmethoxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1-pyridin-4-ylmethyl-1H-indol-6-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-Furan-2-yl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-(2-Methoxy-1,1-dimethyl-ethyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   6-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    {3-[6-(3-amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-hydroxy-benzoic    acid;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-3-nitro-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   5-Ethyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-Azetidin-1-yl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-3-methoxy-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methoxy-benzoic    acid;-   1,4,4-Trimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   4-(1-Methoxy-1-methyl-ethyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-(2,2-Dimethyl-propionyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{6-[3-methoxy-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methoxy-N-(3-methoxy-propyl)-benzamide;-   N-{3-[6-(3-Acryloylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-{3-[6-(1H-indol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-[3-(6-{4-[(2-methoxy-ethylamino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-{3-[6-(4-ethylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(4-diethylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-[3-(6-{4-[(isopropyl-methyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-methyl-piperidin-1-ylmethyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[2-(tetrahydro-pyran-4-ylamino)-ethyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide;-   5-Amino-2-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-cyclopropyl-benzamide;-   5-Amino-benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   2-Amino-N-{3-[6-(benzothiazol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-piperidin-1-yl-benzamide;-   4-tert-Butyl-N-[3-(6-{2-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-4-ylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-(3-{6-[3-methoxy-4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-hydroxy-ethyl)-2-methoxy-N-methyl-benzamide;-   4-tert-Butyl-N-(3-{6-[3-methoxy-4-(piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   N-{3-[6-(3-Amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   N-{3-[6-(4-Amino-2-piperidin-1-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   (4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzylamino)-acetic    acid;-   4-tert-Butyl-N-[3-(6-{4-[(cyclopropylmethyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   N-{3-[6-(3-Amino-4-thiomorpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperidin-3-ylmethoxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-(3-{6-[3-Amino-4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1,2,3,4-tetrahydro-isoquinolin-6-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-[3-(6-{4-[2-(4-ethyl-piperazin-1-yl)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-[3-(6-{4-[2-(2-hydroxy-ethylamino)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-{3-[6-(4-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-(3-{6-[4-(2-diethylamino-ethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-hydroxy-ethyl)-N-methyl-benzamide;-   4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-(3-Methoxymethoxy-piperidin-1-yl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-hydroxymethyl-3-methoxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(1H-indol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   N-(3-{6-[3-Amino-4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-dimethylamino-ethyl)-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[6-(4-morpholin-4-yl-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-morpholin-4-yl-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   N-{3-[6-(3-Amino-4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-diethylamino-ethyl)-benzamide;-   4-tert-Butyl-N-(3-{4-ethyl-6-[4-(phenyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-(3-{4-ethyl-6-[4-(2-methyl-phenyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;-   4-tert-Butyl-N-{3-[6-(4-cyclopropylaminomethyl-3-methoxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(4-cyclopropylaminomethyl-3-methoxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   4-tert-Butyl-N-{3-[6-(3-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   N-(3-{6-[3-Amino-4-(1-oxo-1λ⁴-thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4-(1-Methyl-cyclobutyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-{3-[6-(4-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-[3-(6-{3-[2-(2-hydroxy-ethylamino)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[3-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   4-tert-Butyl-N-[3-(6-{3-[2-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   4-tert-Butyl-N-[3-(6-{3-[2-(4-ethyl-piperazin-1-yl)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;-   N-{3-[6-(3-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-tert-Butyl-N-{3-[6-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   N-(3-{6-[4-(4-Aminomethyl-4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic    acid;-   5-(3-Amino-2-methyl-phenyl)-1-methyl-3-(4-morpholin-4-yl-3-nitro-phenylamino)-1H-pyrazin-2-one;-   5-tert-Butyl-pyridine-2-carboxylic acid    {3-[6-(3-amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    {3-[6-(3-amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;-   N-{3-[6-(3-Amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-piperidin-1-yl-benzamide;-   N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-methylsulfanyl-benzamide;-   N-{3-[6-(3-Amino-4-cyclopropylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-(3-{6-[3-Amino-4-(thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-pyridin-3-yl-benzamide;-   N-(5-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-methoxy-ethyl)-N-methyl-benzamide;-   Octahydro-isoquinoline-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-6-tert-butyl-nicotinamide;-   N-{3-[6-(2-Amino-indan-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-4-tert-butyl-benzamide;-   N-{3-[6-(3-Amino-4-methoxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   1-(2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-piperidine-4-carboxylic    acid amide;-   N-{3-[6-(3-Amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-fluoro-phenyl}-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[4-(4-Aminomethyl-4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[4-(1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-pentafluoroethyl-benzamide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    {2-methyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-amide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-amide;-   N-{3-[6-(3-Amino-4-[1,4]oxazepan-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-[3-(6-{3-Amino-4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;-   4-tert-Butyl-N-{3-[6-(3-methoxy-4-morpholin-4-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   N-(3-{6-[3-Amino-4-(4-hydroxy-4-methyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(2-morpholin-4-yl-ethoxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-[3-(6-{3-Amino-4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methyl-benzoic    acid methyl ester;-   4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methyl-benzoic    acid;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-amide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(3-methyl-4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    [2-methyl-3-(4-methyl-5-oxo-6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-amide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-[1,4]oxazepan-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    {3-[6-(4-hydroxymethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    [3-(6-{4-[(carbamoylmethyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   1-(2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-4-hydroxy-pyridinium;-   N-[3-(6-{3-Amino-4-[(2-hydroxy-ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;-   N-(3-{6-[3-Amino-4-(4-methyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;    and-   5,6,7,8-Tetrahydro-naphthalene-2-carboxylic acid    (2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide,-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    [2-methyl-3-(4-methyl-5-oxo-6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-amide;-   4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-[1,4]oxazepan-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    {3-[6-(4-hydroxymethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    [3-(6-{4-[(carbamoylmethyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide;-   5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   1-(2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-4-hydroxy-pyridinium;-   N-[3-(6-{3-Amino-4-[(2-hydroxy-ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;-   N-(3-{6-[3-Amino-4-(4-methyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-(3-{6-[3-Amino-4-(3-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(3-hydroxy-pyrrolidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-{3-[6-(3-Amino-4-piperidin-1-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;-   4-(2-Hydroxy-1,1-dimethyl-ethyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   1-[2-Amino-4-(4-methyl-6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoyl]-piperidine-4-carboxylic    acid amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(3-hydroxy-pyrrolidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(3-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   N-(3-{6-[3-Amino-4-(4-methyl-[1,4]diazepan-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(4-hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   1-[2-Amino-4-(4-methyl-6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-phenyl]-piperidine-4-carboxylic    acid amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    (3-{6-[3-amino-4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    [3-(6-{3-amino-4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[3-nitro-4-(pyridin-3-yloxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;-   N-[3-(6-{3-Amino-4-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    {2-methyl-3-[4-methyl-5-oxo-6-(pyridin-3-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-amide;-   4-tert-Butyl-N-{3-[6-(3-fluoro-4-morpholin-4-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;-   N-(3-{6-[3-Amino-4-(4-methoxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(4-cyano-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   1-[2-Amino-4-(4-methyl-6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-phenyl]-piperidine-3-carboxylic    acid amide;-   N-(3-{6-[3-Amino-4-(3-hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;-   N-(3-{6-[3-Amino-4-(3-methyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;    and-   4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid    {2-methyl-3-[4-methyl-5-oxo-6-(pyridin-4-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-amide,    and pharmaceutically acceptable salts, solvates, chelates,    non-covalent complexes, prodrugs, and mixtures thereof.

Methods for obtaining the novel compounds described herein will beapparent to those of ordinary skill in the art, suitable proceduresbeing described, for example, in the reaction scheme and examples below,and in the references cited herein.

Referring to Reaction Scheme 1, Step 1, to a suspension of3,5-dibromo-1H-pyridin-2-one and powdered potassium carbonate in aninert solvent such as DMF is added an excess (such as about 1.1equivalents) of a compound of Formula R₁₆-Q wherein Q is a leavinggroup, such as halo. The mixture is stirred at room temperature undernitrogen for about 18 h. The product, a compound of Formula 103, isisolated and optionally purified.

Referring to Reaction Scheme 1, Step 2, to a solution of a compound ofFormula 103 in an inert solvent such as toluene is added an excess (suchas about 1.2 equivalents) of a compound of formula NH₂—B-L-G, about 0.07equivalent of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, about0.05 equivalent of tris(dibenzylideneacetone)dipalladium(0), and anexcess (such as about 1.4 equivalents) of cesium carbonate. The reactiontube is sealed and heated at about 120° C. for about 2 d. The product, acompound of Formula 105, is isolated and optionally purified.

Referring to Reaction Scheme 1, Step 3, a mixture of a compound ofFormula 105 and an excess (such as about 1.1 equivalents) of a compoundof Formula 207, shown below in Reaction Scheme 2; 0.1 equivalent oftetrakis(triphenylphosphine)palladium; and a base such as 1N sodiumcarbonate in an inert solvent such as 1,2-dimethoxyethane is heated atabout 100° C. in a sealed pressure vessel for about 16 h. The product, acompound of Formula 107, is isolated and optionally purified.

Referring to Reaction Scheme 2, Step 1, to a suspension of a compound ofFormula 201, bis(pinacolato)diboron, and a base such as potassiumacetate is added about 0.03 equivalent of [1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex withdichloromethane (1:1). The reaction is heated at about 85° C. for forabout 20 h. The product, a compound of Formula 203, is isolated andoptionally purified.

Referring to Reaction Scheme 2, Step 2, 10% palladium on charcoal isadded to a mixture of a compound of Formula 203 in a polar, proticsolvent such as methanol. To the mixture is added hydrogen gas. Thereaction is stirred under balloon pressure of hydrogen at roomtemperature for about 13 h. The product, a compound of Formula 205, isisolated and optionally purified.

Referring to Reaction Scheme 2, Step 3, a solution of about anequivalent of a compound of formula 206 in an inert solvent such asdichloromethane is added portionwise to a solution of a compound ofFormula 205 and a base such as triethylamine in an inert solvent such asdichloromethane. The mixture is stirred at room temperature for about 16h. The product, a compound of Formula 207, is isolated and optionallypurified.

Referring to Reaction Scheme 3, Step 1, a mixture of a compound ofFormula 301; an excess (such as about 1.2 equivalents) of bis(neopentylglycolato)diboron; and about 0.3 equivalent of[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium, 1:1 complexwith dichloromethane; and a base such as potassium acetate in an inertsolvent such as dioxane is heated at reflux for about 3 h. The product,a compound of Formula 303, is isolated and optionally purified.

Referring to Reaction Scheme 3, Step 2, a mixture of a compound ofFormula 303 and 10% palladium-on-carbon in an inert solvent such asethyl acetate methanol is treated with 40 psi of hydrogen for about 2 hat room temperature. The product, a compound of Formula 305, is isolatedand optionally purified.

Referring to Reaction Scheme 3, Step 3, a solution of a compound ofFormula 305 and a base, such as triethylamine in an inert solvent suchas THF is treated dropwise with about an equivalent of an acid chlorideof the formula 306 and the mixture is stirred at room temperature forabout 15 min. The product, a compound of Formula 307, is isolated andoptionally purified.

Referring to Reaction Scheme 4, Step 1, a mixture of a compound ofFormula 501, about an equivalent of a compound of NH₂—B-L-G, and aninert base such as 1-methyl-2-pyrollidinone is heated at about 130° C.for about 1 hr. The product, a compound of Formula 503, is isolated andoptionally purified.

Referring to Reaction Scheme 4, Step 2, a mixture of a compound ofFormula 503, an excess (such as about 1.2 equivalents) of a compound ofFormula 107, about 0.05 equivalent oftetrakis(triphenylphosphine)palladium and a base such as 1N sodiumcarbonate in an inert solvent such as 1,2-dimethoxyethane is heated atabout 100° C. in a sealed pressure vessel for about 16 hr. The product,a compound of Formula 505, is isolated and optionally purified.

In some embodiments, the chemical entities described herein areadministered as a pharmaceutical composition or formulation.Accordingly, the invention provides pharmaceutical formulationscomprising at least one chemical entity chosen from compounds of Formula1 and pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, prodrugs, and mixtures thereof, together with atleast one pharmaceutically acceptable vehicle chosen from carriers,adjuvants, and excipients.

Pharmaceutically acceptable vehicles must be of sufficiently high purityand sufficiently low toxicity to render them suitable for administrationto the animal being treated. The vehicle can be inert or it can possesspharmaceutical benefits. The amount of vehicle employed in conjunctionwith the chemical entity is sufficient to provide a practical quantityof material for administration per unit dose of the chemical entity.

Exemplary pharmaceutically acceptable carriers or components thereof aresugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; synthetic oils; vegetable oils,such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil;polyols such as propylene glycol, glycerine, sorbitol, mannitol, andpolyethylene glycol; alginic acid; phosphate buffer solutions;emulsifiers, such as the TWEENS; wetting agents, such as sodium laurylsulfate; coloring agents; flavoring agents; tableting agents;stabilizers; antioxidants; preservatives; pyrogen-free water; isotonicsaline; and phosphate buffer solutions.

Optional active agents may be included in a pharmaceutical composition,which do not substantially interfere with the activity of the chemicalentity of the present invention.

Effective concentrations of at least one chemical entity chosen fromcompounds of Formula 1 and pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, prodrugs, and mixtures thereof, aremixed with a suitable pharmaceutical acceptable vehicle. In instances inwhich the chemical entity exhibits insufficient solubility, methods forsolubilizing compounds may be used. Such methods are known to those ofskill in this art, and include, but are not limited to, usingcosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such asTWEEN, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the chemical entity described herein, theresulting mixture may be a solution, suspension, emulsion or the like.The form of the resulting mixture depends upon a number of factors,including the intended mode of administration and the solubility of thechemical entity in the chosen vehicle. The effective concentrationsufficient for ameliorating the symptoms of the disease treated may beempirically determined.

Chemical entities described herein may be administered orally,topically, parenterally, intravenously, by intramuscular injection, byinhalation or spray, sublingually, transdermally, via buccaladministration, rectally, as an ophthalmic solution, or by other means,in dosage unit formulations.

Dosage formulations suitable for oral use, include, for example,tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agents, suchas sweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide pharmaceutically elegant and palatablepreparations. In some embodiments, oral formulations contain from 0.1 to99% of at least one chemical entity described herein. In someembodiments, oral formulations contain at least 5% (weight %) of atleast one chemical entity described herein. Some embodiments containfrom 25% to 50% or from 5% to 75% of at least one chemical entitydescribed herein.

Orally administered compositions also include liquid solutions,emulsions, suspensions, powders, granules, elixirs, tinctures, syrups,and the like. The pharmaceutically acceptable carriers suitable forpreparation of such compositions are well known in the art. Oralformulations may contain preservatives, flavoring agents, sweeteningagents, such as sucrose or saccharin, taste-masking agents, and coloringagents.

Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol, or sucrose. Such formulations may also contain ademulcent.

Chemical entities described herein can be incorporated into oral liquidpreparations such as aqueous or oily suspensions, solutions, emulsions,syrups, or elixirs, for example. Moreover, formulations containing thesechemical entities can be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations can contain conventional additives, such as suspendingagents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup,gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminumstearate gel, and hydrogenated edible fats), emulsifying agents (e.g.,lecithin, sorbitan monsoleate, or acacia), non-aqueous vehicles, whichcan include edible oils (e.g., almond oil, fractionated coconut oil,silyl esters, propylene glycol and ethyl alcohol), and preservatives(e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).

For a suspension, typical suspending agents include methylcellulose,sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80;and typical preservatives include methyl paraben and sodium benzoate.

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents; naturally-occurring phosphatides, forexample, lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example peanut oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or peanut oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

Tablets typically comprise conventional pharmaceutically acceptableadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, can beuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components oftendepends on secondary considerations like taste, cost, and shelfstability.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the chemical entity isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents that have been mentioned above. The sterileinjectable preparation may also be sterile injectable solution orsuspension in a non-toxic parentally acceptable vehicle, for example asa solution in 1,3-butanediol. Among the acceptable vehicles that may beemployed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid can be useful in the preparation ofinjectables.

Chemical entities described herein may be administered parenterally in asterile medium. Parenteral administration includes subcutaneousinjections, intravenous, intramuscular, intrathecal injection orinfusion techniques. Chemical entities described herein, depending onthe vehicle and concentration used, can either be suspended or dissolvedin the vehicle. Advantageously, adjuvants such as local anesthetics,preservatives and buffering agents can be dissolved in the vehicle. Inmany compositions for parenteral administration the carrier comprises atleast 90% by weight of the total composition. In some embodiments, thecarrier for parenteral administration is chosen from propylene glycol,ethyl oleate, pyrrolidone, ethanol, and sesame oil.

Chemical entites described herein may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at rectal temperature and will therefore melt in the rectum torelease the drug. Such materials include cocoa butter and polyethyleneglycols.

Chemical entities described herein may be formulated for local ortopical application, such as for topical application to the skin andmucous membranes, such as in the eye, in the form of gels, creams, andlotions and for application to the eye. Topical compositions may be inany form including, for example, solutions, creams, ointments, gels,lotions, milks, cleansers, moisturizers, sprays, skin patches, and thelike.

Such solutions may be formulated as 0.01%-10% isotonic solutions, pH5-7, with appropriate salts. Chemical entities described herein may alsobe formulated for transdermal administration as a transdermal patch.

Topical compositions comprising at least one chemical entity describedherein can be admixed with a variety of carrier materials well known inthe art, such as, for example, water, alcohols, aloe vera gel,allantoin, glycerine, vitamin A and E oils, mineral oil, propyleneglycol, PPG-2 myristyl propionate, and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows:

Representative emollients include stearyl alcohol, glycerylmonoricinoleate, glyceryl monostearate, propane-1,2-diol,butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate,stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol,isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetylalcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate,iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butylstearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil,coconut oil, arachis oil, castor oil, acetylated lanolin alcohols,petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid,isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, andmyristyl myristate; propellants, such as propane, butane, iso-butane,dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such asethyl alcohol, methylene chloride, iso-propanol, castor oil, ethyleneglycol monoethyl ether, diethylene glycol monobutyl ether, diethyleneglycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide,tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, andgelatin; and powders, such as chalk, talc, fullers earth, kaolin,starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkyl ammonium smectites, trialkyl aryl ammonium smectites, chemicallymodified magnesium aluminium silicate, organically modifiedmontmorillonite clay, hydrated aluminium silicate, fumed silica,carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethyleneglycol monostearate.

Chemical entities described herein may also be topically administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine and phosphatidylcholines.

Other compositions useful for attaining systemic delivery of thechemical entity include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol, and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropylmethylcellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions for inhalation typically can be provided in the form of asolution, suspension or emulsion that can be administered as a drypowder or in the form of an aerosol using a conventional propellant(e.g., dichlorodifluoromethane or trichlorofluoromethane).

The compositions of the present invention may also optionally comprisean activity enhancer. The activity enhancer can be chosen from a widevariety of molecules that function in different ways to enhance or beindependent of therapeutic effects of the chemical entities describedherein. Particular classes of activity enhancers include skinpenetration enhancers and absorption enhancers.

Pharmaceutical compositions of the invention may also contain additionalactive agents that can be chosen from a wide variety of molecules, whichcan function in different ways to enhance the therapeutic effects of atleast one chemical entity described herein. These optional other activeagents, when present, are typically employed in the compositions of theinvention at a level ranging from 0.01% to 15%. Some embodiments containfrom 0.1% to 10% by weight of the composition. Other embodiments containfrom 0.5% to 5% by weight of the composition.

The invention includes packaged pharmaceutical formulations. Suchpackaged formulations include a pharmaceutical composition comprising atleast one chemical entity chosen from compounds of Formula 1 andpharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, and instructions for usingthe composition to treat a mammal (typically a human patient). In someembodiments, the instructions are for using the pharmaceuticalcomposition to treat a patient suffering from a disease responsive toinhibition of Btk activity and/or inhibition of B-cell activity. Theinvention can include providing prescribing information; for example, toa patient or health care provider, or as a label in a packagedpharmaceutical formulation. Prescribing information may include forexample efficacy, dosage and administration, contraindication andadverse reaction information pertaining to the pharmaceuticalformulation.

In all of the foregoing the chemical entities can be administered alone,as mixtures, or in combination with other active agents.

Accordingly, the invention includes a method of treating a patient, forexample, a mammal, such as a human, having a disease responsive toinhibition of Btk activity, comprising administrating to the patienthaving such a disease, an effective amount of at least one chemicalentity chosen from compounds of Formula 1 and pharmaceuticallyacceptable salts, solvates, chelates, non-covalent complexes, prodrugs,and mixtures thereof.

To the extent that Btk is implicated in disease, alleviation of thedisease, disease symptoms, preventative, and prophylactic treatment iswithin the scope of this invention. In some embodiments, the chemicalentities described herein may also inhibit other kinases, such thatalleviation of disease, disease symptoms, preventative, and prophylactictreatment of conditions associated with these kinases is also within thescope of this invention.

Methods of treatment also include inhibiting Btk activity and/orinhibiting B-cell activity, by inhibiting ATP binding or hydrolysis byBtk or by some other mechanism, in vivo, in a patient suffering from adisease responsive to inhibition of Btk activity, by administering aneffective concentration of at least one chemical entity chosen fromcompounds of Formula 1 and pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, prodrugs, and mixtures thereof. Anexample of an effective concentration would be that concentrationsufficient to inhibit Btk activity in vitro. An effective concentrationmay be ascertained experimentally, for example by assaying bloodconcentration of the chemical entity, or theoretically, by calculatingbioavailability.

In some embodiments, the condition responsive to inhibition of Btkactivity and/or B-cell activity is cancer, an allergic disorder and/oran autoimmune and/or inflammatory disease, and/or an acute inflammatoryreaction.

The invention includes a method of treating a patient having cancer, anallergic disorder and/or an autoimmune and/or inflammatory disease,and/or an acute inflammatory reaction, by administering an effectiveamount of at least one chemical entity chosen from compounds of Formula1 and pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, prodrugs, and mixtures thereof.

In some embodiments, the conditions and diseases that can be affectedusing chemical entities described herein, include, but are not limitedto:

allergic disorders, including but not limited to eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions;

autoimmune and/or inflammatory diseases, including but not limited topsoriasis, Crohn's disease, irritable bowel syndrome, Sjogren's disease,tissue graft rejection, and hyperacute rejection of transplanted organs,asthma, systemic lupus erythematosus (and associatedglomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma,vasculitis (ANCA-associated and other vasculitides), autoimmunehemolytic and thrombocytopenic states, Goodpasture's syndrome (andassociated glomerulonephritis and pulmonary hemorrhage),atherosclerosis, rheumatoid arthritis, chronic Idiopathicthrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease,Alzheimer's disease, diabetes, septic shock, myasthenia gravis, and thelike,

acute inflammatory reactions, including but not limited to skin sunburn,inflammatory pelvic disease, inflammatory bowel disease, urethritis,uvitis, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, and cholocystitis,and

cancer, including but not limited to, B-cell lymphoma, lymphoma(including Hodgkin's and non-Hodgkins lymphoma), hairy cell leukemia,multiple myeloma, chronic and acute myelogenous leukemia, and chronicand acute lymphocytic leukemia.

Btk is a known inhibitor of apoptosis in lymphoma B-cells. Defectiveapoptosis contributes to the pathogenesis and drug resistance of humanleukemias and lymphomas. Thus, further provided is a method of promotingor inducing apoptosis in cells expressing Btk comprising contacting thecell with at least one chemical entity chosen from compounds of Formula1 pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof.

The invention provides methods of treatment in which at least onechemical entity chosen from compounds of Formula 1 pharmaceuticallyacceptable salts, solvates, chelates, non-covalent complexes, prodrugs,and mixtures thereof, is the only active agent given to a patient andalso includes methods of treatment in which at least one chemical entitychosen from compounds of Formula 1 and pharmaceutically acceptablesalts, solvates, chelates, non-covalent complexes, prodrugs, andmixtures thereof, is given to a patient in combination with one or moreadditional active agents.

Thus in one embodiment the invention provides a method of treatingcancer, an allergic disorder and/or an autoimmune and/or inflammatorydisease, and/or an acute inflammatory reaction, which comprisesadministering to a patient in need thereof an effective amount of atleast one chemical entity chosen from compounds of Formula 1 andpharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, together with a second activeagent, which can be useful for treating a cancer, an allergic disorderand/or an autoimmune and/or inflammatory disease, and/or an acuteinflammatory reaction. For example the second agent may be ananti-inflammatory agent. Treatment with the second active agent may beprior to, concomitant with, or following treatment with at least onechemical entity chosen from compounds of Formula 1 and pharmaceuticallyacceptable salts, solvates, chelates, non-covalent complexes, prodrugs,and mixtures thereof. In certain embodiments, at least one chemicalentity chosen from compounds of Formula 1 and pharmaceuticallyacceptable salts, solvates, chelates, non-covalent complexes, prodrugs,and mixtures thereof, is combined with another active agent in a singledosage form. Suitable antitumor therapeutics that may be used incombination with at least one chemical entity described herein include,but are not limited to, chemotherapeutic agents, for example mitomycinC, carboplatin, taxol, cisplatin, paclitaxel, etoposide, doxorubicin, ora combination comprising at least one of the foregoing chemotherapeuticagents. Radiotherapeutic antitumor agents may also be used, alone or incombination with chemotherapeutic agents.

Chemical entities described herein can be useful as chemosensitizingagents, and, thus, can be useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.

A method for increasing sensitivity of cancer cells to chemotherapy,comprising administering to a patient undergoing chemotherapy achemotherapeutic agent together with at least one chemical entity chosenfrom compounds of Formula 1 and pharmaceutically acceptable salts,solvates, chelates, non-covalent complexes, prodrugs, and mixturesthereof, in an amount sufficient to increase the sensitivity of cancercells to the chemotherapeutic agent is also provided herein.

Examples of other chemotherapeutic drugs that can be used in combinationwith chemical entities described herein include topoisomerase Iinhibitors (camptothesin or topotecan), topoisomerase II inhibitors(e.g. daunomycin and etoposide), alkylating agents (e.g.cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g.taxol and vinblastine), and biological agents (e.g. antibodies such asanti CD20 antibody, IDEC 8, immunotoxins, and cytokines).

Included herein are methods of treatment in which at least one chemicalentity chosen from compounds of Formula 1 and pharmaceuticallyacceptable salts, solvates, chelates, non-covalent complexes, prodrugs,and mixtures thereof, is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be chosen from cortisone, dexamethasone,methylprednisolone, prednisolone, prednisolone sodium phosphate, andprednisone.

In additional embodiments the anti-inflammatory therapeutic agent is agold compound such as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-C5 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asmethotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, ormycophenolate mofetil.

Dosage levels of the order, for example, of from 0.1 mg to 140 mg perkilogram of body weight per day can be useful in the treatment of theabove-indicated conditions (0.5 mg to 7 g per patient per day). Theamount of active ingredient that may be combined with the vehicle toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Dosage unit forms willgenerally contain from 1 mg to 500 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. In some embodiments, for example, for thetreatment of an allergic disorder and/or autoimmune and/or inflammatorydisease, a dosage regimen of 4 times daily or less is used. In someembodiments, a dosage regimen of 1 or 2 times daily is used. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular diseasein the patient undergoing therapy.

A labeled form of a compound of the invention can be used as adiagnostic for identifying and/or obtaining compounds that have thefunction of modulating an activity of a kinase as described herein. Thecompounds of the invention may additionally be used for validating,optimizing, and standardizing bioassays.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 14-tert-Butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide

3,5-Dibromo-1-methyl-1H-pyridin-2-one (1)

A 1-L round-bottomed flask equipped with a magnetic stirrer was chargedwith 3,5-dibromo-1H-pyridin-2-one (7.0 g, 27.7 mmol), anhydrous DMF (280mL) and powdered potassium carbonate (−350 mesh, 8.4 g, 61.1 mmol), andthe suspension stirred for 15 min at ambient temperature. After thistime, methyl iodide (4.3 g, 30.5 mmol) was added, and the mixture wasstirred at room temperature under nitrogen for a further 18 h. Thereaction mixture was then diluted with water (200 mL), extracted withethyl acetate (3×250 mL), dried over sodium sulfate and concentrated invacuo. The resulting residue was purified by flash chromatography onsilica to give an 84% yield (6.2 g) of3,5-dibromo-1-methyl-1H-pyridin-2-one (1) as an off-white solid: mp87-88° C.; MS (ESI+) m/z 266 (M+H).

4-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-benzoic acidethyl ester (2)

A solution of 3,5-dibromo-1-methyl-1Hpyridin-2-one (1) (990 g; 3.7 mmol)in toluene (12 mL) was sparged with argon for 15 minutes. Ethyl4-aminobenzoate (740 mg; 4.5 mmol),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (170 mg, 0.28 mmol),tris(dibenzylideneacetone)dipalladium(0) (170 mg, 0.19 mmol) and cesiumcarbonate (1.7 g, 5.2 mmol) were then added. The reaction tube was thensealed and heated at 120° C. for 2 d. The mixture was cooled to roomtemperature, diluted with water (50 mL) and extracted with EtOAc (3×50mL). The combined organic layers were washed with and brine (1×100 mL),dried over sodium sulfate and concentrated in vacuo. The crude residuewas purified by flash chromatography (9:1-1:1, hexanes/EtOAc, gradient)to give 4-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-benzoicacid ethyl ester (2) as a light brown solid (380 mg).

4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (3)

A 1-L three-neck round-bottomed flask equipped with a mechanical stirrerand thermoregulator was purged with nitrogen and charged with2-bromo-6-nitrotoluene (60.2 g; 278 mmol), bis(pinacolato)diboron (85.2g; 336 mmol), potassium acetate (82.4 g; 840 mmol) and DMSO (320 mL). Astream of nitrogen was passed through the resulting suspension for 30min, [1,1′ bis(diphenylphosphino)-ferrocene]dichloropalladium (II),complex with dichloromethane (1:1) (7.60 g; 9.30 mmol) was then addedand the reaction heated at 85° C. for 20 h. After this time the mixturewas cooled to ambient temperature, poured into a mixture of water (1300mL) and MtBE (500 mL) and treated with Cellpure P65 (150 cc). Theresulting suspension was filtered through a pad of Cellpure P65 (200 cc)packed onto a fritted funnel (ID 185 mm). The filter cake was washedwith MtBE (3×180 mL) and the organic layer of the filtrate separated,washed with water (3×1 L) and dried over sodium sulfate. After filteringoff sodium sulfate, the filtrate was concentrated and purified by flashchromatography to afford4,4,5,5-tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (3)as a light yellow solid: mp 52-53° C.; MS (APCI+) m/z 264 (M+H).

2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(4)

A 500-mL round-bottomed flask equipped with a magnetic stirrer wascharged with4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (3)(8.44 g; 32.1 mmol) and methanol (150 mL). The reaction flask was twiceevacuated and back-filled with argon. 10% Palladium on charcoal (50%wet, 425 mg dry weight) was then added to the solution, and the reactionflask evacuated and back-filled with hydrogen three times. The reactionwas then stirred under balloon pressure of hydrogen at room temperaturefor 13 h. After this time, the flask was twice evacuated and back-filledwith argon, then filtered through a pad of Celite 521 and the filtrateconcentrated in vacuo. The resulting residue was dried under high vacuumfor 1 d to afford a quantitative yield (8.16 g) of2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(4) as a white solid: mp 110-112° C.; MS (ESI+) m/z 234 (M+H).

4-tert-Butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(5)

A solution of 4-tert-butylbenzoyl chloride (5.24 g; 26.7 mmol) indichloromethane (40 mL) was added portionwise to a solution of2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(4) (6.22 g; 26.7 mmol) and triethylamine (5.6 mL; 40.1 mmol) indichloromethane (60 mL) and the mixture was stirred at room temperaturefor 16 hr. Water (100 mL) was added and the mixture extracted withdichloromethane (3×70 mL). The combined organic layers were washed withwater (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate andevaporated under reduced pressure to give4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(5) as a white solid (9.7 g).

4-{5-[3-(4-tert-Butyl-benzoylamino)-2-methylphenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-benzoicacid ethyl ester (6)

A mixture of4-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-benzoic acidethyl ester (2) (380 mg; 1.1 mmol),4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(5) (510 mg; 1.3 mmol), tetrakis(triphenylphosphine)palladium (130 mg;0.1 mmol), 1N sodium carbonate (1.6 mL; 3.2 mmol), and1,2-dimethoxyethane (8 mL) was heated at 100° C. in a sealed pressurevessel for 16 h. The mixture was cooled to room temperature, treatedwith water (70 mL) and extracted with ethyl acetate (3×60 mL). Thecombined organic extracts were washed with water (1×40 mL) and brine(1×40 mL), dried over sodium sulfate and concentrated in vacuo. Thecrude residue was purified by flash chromatography (3:1-1:3,hexane/EtOAc, gradient) to give4-{5-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoicacid ethyl ester (6) as a brown solid (460 mg).

4-{5-[3-(4-tert-Butyl-benzoylamino)-2-methylphenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoicacid (7)

A mixture of4-{5-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoicacid ethyl ester (6) (460 mg; 0.86 mmol), 1N NaOH (10 mL), and ethanol(10 mL) was heated at reflux for 1.5 h. The mixture was cooled to roomtemperature, the resulting slurry was washed with ethyl acetate (2×40mL), and the ethyl acetate was decanted off. The aqueous slurry wastaken to pH 5 with 1N HCl, filtered, washed with water and then diethylether to yield4-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoicacid (7) as a light brown solid (248 mg), MS 510.34 (M+H).

4-tert-Butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide(8)

A solution of4-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoicacid (7) (56 mg; 0.11 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(58 mg; 0.13 mmol) and N,N-dimethylformamide (2 mL) was stirred at roomtemperature for 0.5 h. 4-Hydroxypiperidine (56 mg; 0.55 mmol) was addedand the mixture was stirred at room temperature for 16 h. Water (15 mL)was added and the mixture was extracted with ethyl acetate (3×30 mL).The combined organic extracts were washed with water (2×30 mL) and brine(1×30 mL), dried over sodium sulfate, and concentrated in vacuo. Theresidue was slurried with diethyl ether and filtered to give4-tert-butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide(8) as a light brown solid (40 mg), MS 593.41 (M+H)

EXAMPLE 2

The following compounds were prepared using procedures similar to thosedescribed in Example 1. Name MS Structure MW m/z

4-tert-Butyl-N-(2-methyl-3-{1- methyl-5-[4-(morpholine-4-carbonyl)-phenylaminol-6-oxo- 1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide 578.70 579.51

4-{5-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2- dihydro-pyridin-3-ylamino}- benzoic acid509.60 510.34

4-tert-Butyl-N-(2-methyl-3-{1- methyl-5-[4-(4-methyl-piperazine-1-carbonyl)- phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)- benzamide 591.7 592.37

4-tert-Butyl-N-(2-methyl-3-{1- methyl-5-[4-(N-methylethanolamine-2-carbonyl)- phenylamino]-6-oxo-1,6-dihydro-pyrazin-3-yl}-phenyl)- benzamide 566.69 567.32

4-tert-Butyl-N-(2-methyl-3-{1- methyl-5-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-6-oxo- 1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide 592.73 593.36

4-tert-Butyl-N-(3-{5-[4-(4- hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo- 1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide 592.73 593.41

N-{3-[5-(3-Amino- phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2- methyl-phenyl}-4-tert-butyl- benzamide480.25 481.17

Tetrahydro-furan-2-carboxylic acid (3-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl- phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}- phenyl)-amine 578.29 578.37

4-tert-Butyl-N-{3-[1,4-dimethyl- 5-(4-morpholin-4-yl-phenylamino)-6-oxo-1,6- dihydro-pyridin-3-yl]-2-methyl-phenyl}-benzamide 564.31 565.37

4-tert-Butyl-N-(3-{5-[4-(1,1- dioxo-116-thiomorpholin-4-yl)-phenylamino]-1-methyl-6-oxo- 1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide 598.26 599.30

EXAMPLE 3A4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide3,5-dibromo-1-methyl-2(1H)pyrazinone (1)

(J. Heterocycl. Chem. 1983, 20, 919)

A 250-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,2-dichlorobenzene (100mL) and oxalyl bromide (60.6 g; 281 mmol). To the solution was addedmethylaminoacetonitrile (7.01 g; 65.8 mmol) and the reaction heatedunder nitrogen to 80° C. After 18 h the resulting mixture was cooled toroom temperature, evaporated under reduced pressure and the resultingresidue purified by flash chromatography to afford3,5-dibromo-1-methyl-2(1H)pyrazinone (1) (2.87 g, 16%) as an off-whitesolid: mp 94-95° C.; MS (ESI+) m/z 267 (M+H).

4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acidethyl ester (2)

A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (1) (21.3 g; 79.5mmol), ethyl 4-aminobenzoate (13.1 g; 79.5 mmol), and1-methyl-2-pyrollidinone (10 mL) was heated at 130 degrees for 1 hr. Themixture was cooled to room temperature, diluted with dichloromethane andfiltered to give a dull brown solid. This was slurried with 0.5N NaOH,filtered, washed with water and diethyl ether to give4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acidethyl ester (2) as a light brown solid (21.3 g)

4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (3)

A 1-L three-neck round-bottomed flask equipped with a mechanical stirrerand thermoregulator was purged with nitrogen and charged with2-bromo-6-nitrotoluene (60.2 g; 278 mmol), bis(pinacolato)diboron (85.2g; 336 mmol), potassium acetate (82.4 g; 840 mmol) and DMSO (320 mL). Astream of nitrogen was passed through the resulting suspension for 30min, [1,1′ bis(diphenylphosphino)-ferrocene]dichloropalladium (II),complex with dichloromethane (1:1) (7.60 g; 9.30 mmol) was then addedand the reaction heated at 85° C. for 20 h. After this time the mixturewas cooled to ambient temperature, poured into a mixture of water (1300mL) and MtBE (500 mL) and treated with Cellpure P65 (150 cc). Theresulting suspension was filtered through a pad of Cellpure P65 (200 cc)packed onto a fritted funnel (ID 185 mm). The filter cake was washedwith MtBE (3×180 mL) and the organic layer of the filtrate separated,washed with water (3×1 L) and dried over sodium sulfate. After filteringoff sodium sulfate, the filtrate was concentrated and purified by flashchromatography to afford4,4,5,5-tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (3)as a light yellow solid: mp 52-53° C.; MS (APCI+) m/z 264 (M+H).

2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(4)

A 500-mL round-bottomed flask equipped with a magnetic stirrer wascharged with4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (3)(8.44 g; 32.1 mmol) and methanol (150 mL). The reaction flask was twiceevacuated and back-filled with argon. 10% Palladium on charcoal (50%wet, 425 mg dry weight) was then added to the solution, and the reactionflask evacuated and back-filled with hydrogen three times. The reactionwas then stirred under balloon pressure of hydrogen at room temperaturefor 13 h. After this time, the flask was twice evacuated and back-filledwith argon, then filtered through a pad of Celite 521 and the filtrateconcentrated in vacuo. The resulting residue was dried under high vacuumfor 1 d to afford a quantitative yield (8.16 g) of2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(4) as a white solid: mp 110-112° C.; MS (ESI+) m/z 234 (M+H).

4-tert-Butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(5)

A solution of 4-tert-butylbenzoyl chloride (5.24 g; 26.7 mmol) indichloromethane (40 mL) was added portionwise to a solution of2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(4) (6.22 g; 26.7 mmol) and triethylamine (5.6 mL; 40.1 mmol) indichloromethane (60 mL) and the mixture was stirred at room temperaturefor 16 hr. Water (100 mL) was added and the mixture extracted withdichloromethane (3×70 mL). The combined organic layers were washed withwater (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate andevaporated under reduced pressure to give4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(5) as a white solid, 9.7 g.

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid ethyl ester (6)

A mixture of4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acidethyl ester (2) (340 mg; 0.97 mmol),4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(5) (457 mg; 1.16 mmol), tetrakis(triphenylphosphine)palladium (56 mg;0.05 mmol), 1N sodium carbonate (2.9 mL; 2.9 mmol), and1,2-dimethoxyethane (30 mL) was heated at 100 degrees in a sealedpressure vessel for 16 hr. The mixture was cooled to room temperature,treated with water (70 mL) and extracted with ethyl acetate (3×60 mL).The combined organic extracts were washed with water (2×40 mL) and brine(1×40 mL), dried over magnesium sulfate, and evaporated under reducedpressure. The resulting residue was triturated with diethylether/dichloromethane to give4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid ethyl ester (6) as a gray solid (330 mg), MS 539.49 (M+H).

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid (7)

A mixture of give4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid ethyl ester (6) (300 mg; 0.56 mmol), 1N NaOH (5 mL), and ethanol (5mL) was heated at reflux for 1 hr. The mixture was cooled to roomtemperature and the resulting slurry was washed with ethyl acetate (2×40mL) and the ethyl acetate was decanted off. The aqueous slurry was takento pH 5 with 1N HCl, filtered, washed with water and then diethyl etherto give4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid (7) as a gray solid (110 mg), MS 511.46 (M+H).

4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide(8)

A solution of4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid (7) (80 mg; 0.16 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(69 mg; 0.16 mmol), N,N-diisopropylethylamine (0.09 mL; 0.48 mmol), andN,N-dimethylformamide (1 mL) was stirred at room temperature for 0.5 hr.N-Methylpiperazine (80 mg; 0.8 mmol) was added and the mixture wasstirred at room temperature for 16 hr. Water (30 mL) was added and themixture was extracted with ethyl acetate (3×60 mL). The combined organicextracts were washed with water (2×30 mL) and brine (1×30 mL), driedover magnesium sulfate, and evaporated under reduced pressure. Theresidue was slurried with diethyl ether and filtered to give4-tert-butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide(8) as a cream solid (50 mg), MS 593.35 (M+H)

EXAMPLE 3B5-Bromo-3-(4-fluoro-3-nitro-phenylamino)-1-methyl-1H-pyrazin-2-one (1)

A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (10 g; 37.5 mmol),4-fluoro-3-nitroaniline (5.9 g; 37.5 mmol), and 1-methyl-2-pyrollidinone(30 mL) was heated at 140 degrees for 1 hr. The mixture was cooled toroom temperature, diluted with ethyl acetate (100 mL) and filtered togive 5-bromo-3-(4-fluoro-3-nitro-phenylamino)-1-methyl-1H-pyrazin-2-one(1) as a yellow solid (8.9 g).

4-tert-Butyl-N-{3-[6-(4-fluoro-3-nitro-phenylamino)₄-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide(2)

A mixture of5-bromo-3-(4-fluoro-3-nitro-phenylamino)-1-methyl-1H-pyrazin-2-one (1)(8.8 g; 25.7 mmol),4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(11.1 g; 28.3 mmol), tetrakis(triphenylphosphine)palladium (1.48 g; 1.28mmol), 1N sodium carbonate (77 mL; 77 mmol), and 1,2-dimethoxyethane(100 mL) was heated at 100 degrees in a sealed pressure vessel for 16hr. The mixture was cooled to room temperature, filtered, and theresidue washed with water (3×60 mL). The solid was slurried with ethylacetate for 1 hr, filtered, and washed with diethyl ether to give4-tert-butyl-N-{3-[6-(4-fluoro-3-nitro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide(2) as a dull yellow solid (13 g).

4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-methylamino-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide(3)

A mixture of give4-tert-butyl-N-{3-[6-(4-fluoro-3-nitro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide(2) (600 mg; 1.13 mmol), methylamine (5 mL of a 2M solution in THF), and1-methyl-2-pyrollidinone (10 mL) was heated at 60 degrees in a sealedpressure vessel for 16 hr. The mixture was cooled to room temperature,treated with water (30 mL) and filtered to give4-tert-butyl-N-{2-methyl-3-[4-methyl-6-(4-methylamino-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide(3) as a red solid (501 mg).

N-{3-[6-(3-Amino-4-methylamino-phenylamino)₄-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide(4)

A mixture of4-tert-butyl-N-{2-methyl-3-[4-methyl-6-(4-methylamino-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide(3) (500 mg), 10% palladium-on-carbon (100 mg), ethanol (50 mL), andethyl acetate (100 mL) was hydrogenated at room temperature and 40 psihydrogen for 16 hr. The mixture was filtered through a celite pad,washing with ethyl acetate (2×100 mL). The combined filtrates wereevaporated to giveN-{3-[6-(3-amino-4-methylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide(4) as a yellow solid (402 mg), m/z 512.08 (MH+).

EXAMPLE 3C 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carbonyl chloride (1)

4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid (1.0 g, 5.50mmol) is dissolved in dichloromethane [DCM] (25 mL) that contains 5drops of N,N-dimethylformamide [DMF] under nitrogen and cooled to 0° C.Oxalyl chloride (13.7 mL of a 2.0M solution in DCM) is added via syringeand allowed to warm to RT over 1 hour. All solvent is then removed underreduced pressure, and the resultant oil is reduced from toluene (3×20mL) to remove residual oxalyl chloride. The residue is then dissolved inethyl acetate and washed with saturated sodium bicarbonate (1×100 mL),then washed with saturated sodium chloride (1×100 mL) and dried oversodium sulfate. The solution is then filtered and concentrated underreduced pressure to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonylchloride (1) as an off-white solid (1.03 g).

4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(2)

2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(1.20 g, 5.16 mmol, 1.0 equiv) and pyridine (0.42 mL, 25.8 mmol) aredissolved in DCM (40 mL) at 0° C. under a nitrogen atmosphere.4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carbonyl chloride (1) (1.03 g,5.16 mmol) is then added in portions over 5 min and allowed to reactwarming to RT over 60 min. All solvent is then removed under reducedpressure, and the resultant oil is reduced from toluene (3×20 mL) toremove residual pyridine. The residue is then dissolved in ethyl acetateand washed with sodium hydroxide (1N, 1×100 mL), then washed withsaturated sodium chloride (1×100 mL) and dried over sodium sulfate. Thesolution is then filtered and concentrated under reduced pressure togive 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(2) as an off-white solid (1.87 g).

4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-2-nitro-benzoicacid (3)

3,5-Dibromo-1-methyl-1H-pyrazin-2-one (1.0 g, 3.73 mmol) and4-amino-2-nitrobenzoic acid (0.68 g, 3.73 mmol) are dissolved inisopropanol (20 mL) and heated at 90° C. for 4 hours. The reaction iscooled to room temperature and the resulting suspension is filtered. Thefilter cake is then washed with ethyl ether (3×100 mL) and air dried togive4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-2-nitro-benzoicacid (3) as a tan solid (1.17 g).

4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-N-(2-hydroxy-ethyl)-N-methyl-2-nitro-benzamide(4)

4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-2-nitro-benzoicacid (3) (1.0 g, 2.72 mmol),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate[BOP] (120 mg, 2.72 mmol,), diisopropylethylamine (1.42 mL, 8.15 mmol)and 2-methylaminoethanol (0.33 mL, 4.07 mmol) are dissolved in DMF (25mL) at room temperature and allowed to react for 60 min. The reaction isquenched by the addition of water (120 mL) and the resulting suspensionwas allowed to stir for 15 min. The suspension is then filtered, washedwith water (3×50 mL) and then air-dried to give4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-N-(2-hydroxy-ethyl)-N-methyl-2-nitro-benzamide(4) as a yellow solid (1.05 g).

4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid[3-(6-{4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-3-nitro-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide(5)

4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-N-(2-hydroxy-ethyl)-N-methyl-2-nitro-benzamide(4) (250 mg, 0.59 mmol, 1.0 equiv),4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylicacid[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(257 mg, 0.65 mmol) and tetrakis(triphenylphosphine)palladium (68 mg,0.06 mmol) are dissolved in 1,4-dioxane (2.0 mL) and sodium carbonate(1N, 1.0 mL) and heated in a microwave glass reactor for 6 minutes at140° C. Once completed the reaction is transferred to a seperatoryfunnel with ethyl acetate (50 mL) and washed with saturated sodiumbicarbonate (1×100 mL), then washed with saturated sodium chloride(1×100 mL) and dried over sodium sulfate. The solution is then filteredand concentrated under reduced pressure. The resulting residue is thentriturated with DCM and hexane to give4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid[3-(6-{4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-3-nitro-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide(5) as a light yellow solid (225 mg).

4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid[3-(6-{3-amino-4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-phenylamino}4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide(6)

4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid[3-(6-{4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-3-nitro-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide(5) (200 mg, 0.32 mmol) is dissolved in a mixture of ethanol (25 mL) andwater (5.0 mL). Ammonium chloride (200 mg, 3.81 mmol) and iron powder(200 mg, 3.58 mmol) are then added and the reaction is allowed toproceed at 95° C. for 30 min. The reaction contents are thenhot-filtered through celite and then transferred to a seperatory funnelwith ethyl acetate (100 mL). The crude solution is then washed withsaturated sodium bicarbonate (1×100 mL), then washed with saturatedsodium chloride (1×100 mL) and dried over sodium sulfate. The solutionis then filtered and concentrated under reduced pressure. The resultingresidue is then triturated with DCM and ethyl ether to give4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid[3-(6-{3-amino-4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide(6) as an off-white solid (135 mg), m/z 587.20 (MH+).

EXAMPLE 3D4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acidethyl ester (1)

A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (21.3 g; 79.5 mmol),ethyl 4-aminobenzoate (13.1 g; 79.5 mmol), and 1-methyl-2-pyrrolidinone(10 mL) was heated at 130 degrees for 1 hr. The mixture was cooled toroom temperature, diluted with dichloromethane and filtered to give adull brown solid. This was slurried with 0.5N NaOH, filtered, washedwith water and diethyl ether to give4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acidethyl ester (1) as a light brown solid (21.3 g)

5-Bromo-3-(4-hydroxymethyl-phenylamino)-1-methyl-1H-pyrazin-2-one (2)

A slurry of4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acidethyl ester (1) (7.75 g; 22.02 mmol) in CH₂Cl₂ (200 mL) was cooled to−78° C. under N₂. A solution of DIBAL-H (100 mL; 1.0 M in CH₂Cl₂) wasadded dropwise over 30 min. to the stirring slurry, and the reactionallowed to warm gradually to rt over 30 min. The reaction stirred for 1hr at rt, and was monitored by LC-MS until only product was observed.The reaction was cooled to 0° C. in an ice bath and was quenched by slowaddition of 1.0 N NaOH (75 mL). The reaction bilayer was extracted withEtOAc (5×100 mL) and the EtOAc layers were pooled, washed with brine anddried over solid Na₂SO₄. After filtering off the solids, the filtratewas evaporated down to an orange-red oil, which was then redissolved in3 mL CH₂Cl₂ and triturated slowly with diethyl ether (20 mL) to provide5-bromo-3-(4-hydroxymethyl-phenylamino)-1-methyl-1H-pyrazin-2-one (2) asa light orange solid (3.1 g). MS 311.25 & 313.20 (M+H)

4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzaldehyde(3)

Compound (2) (3.1 g; 10 mmol) was dissolved in 150 mL CH₂Cl₂ at rt underN₂. Solid 12 (5.1 g; 20 mmol) was added portion-wise to the stirringreaction, followed by catalytic 2,2,6,6-tetramethyl-1-piperdinyloxy,free radical (TEMPO; 0.23 g; 1.50 mmol). Saturated sodium bicarbonatesolution was then added (20 mL) and the reaction allowed to stirovernight at rt under N₂. The resulting light orange solid was filteredoff and washed repeatedly with CH₂Cl₂ and diethyl ether until theextractions ran clear and colorless. After drying,4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzaldehyde(3) was obtained in nearly quantitative yields (3.1 g) and was carrieddirectly on to the next reaction. MS 308.01 & 310.01 (M+H)

4-tert-Butyl-N-{3-[6-(4-formyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide(4)

A mixture of4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzaldehyde(3) (2.0 g; 6.51 mmol),4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(3.28 g; 7.8 mmol), tetrakis(triphenylphosphine)palladium (0.75 g; 0.65mmol), 1N sodium carbonate (16.0 mL), and 1,2-dimethoxyethane (50 mL)was heated at 95° C. in a sealed pressure vessel for 12 hr. The mixturewas cooled to room temperature, treated with water (70 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith water (2×75 mL) and brine (1×75 mL), dried over solid sodiumsulfate, and evaporated under reduced pressure. The resulting residuewas triturated with diethyl ether/dichloromethane to give4-tert-butyl-N-{3-[6-(4-formyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide(4) as a light gray solid (3.6 g), MS 495.35 (M+H).

N-{3-[6-(4-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-phenylamino)₄-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}4-tert-butyl-benzamide(5)

4-tert-butyl-N-{3-[6-(4-formyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide(4) (110 mg; 0.22 mmol) was dissolved in methanol (10 mL) and 1 mL2-(2-hydroxy-ethylamino)-ethanol was added. To the stirring reactionsolution was then added 0.25 mL glacial acetic acid, followed by 0.25 gpowdered molecular sieves (4 Å; activated) and the resulting slurryallowed to stir at rt for 4 hr under N₂, then heated to 50° C. After 3hr at 50° C., the reaction was cooled to rt and excess NaBH₄ powder (0.5g) was added portionwise to the stirring slurry. After gas evolutionceased, the reaction slurry was then adsorbed directly onto silica geland was chromatographed using methanol/CH₂Cl₂ (1:9) as eluent to provideN-{3-[6-(4-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide(5) (75 mg) as an off-white solid. MS 584.24 (M+H).

EXAMPLE 3E5-Bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one(1)

A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (2.0 g; 7.5 mmol),2-(4-Amino-phenyl)-ethanol (1.0 g; 7.3 mmol), and1-methyl-2-pyrrolidinone (1 mL) was heated at 120° C. for 1 hr. Themixture was cooled to room temperature, diluted with dichloromethane andfiltered to give a dull brown oil. This was dissolved in CH₂Cl₂ andwashed with 0.01N NaOH, and dried over solid sodium sulfate. Afterfiltration and evaporation of the CH₂Cl₂ layer, the resulting brownsolid was chromatographed on silica using methanol/CH₂Cl₂ (1:9) aseluent to provide 2.0 g of5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one(1) as a light tan solid. MS 324.23 (M+H).

4-tert-Butyl-N-(3-{6-[4-(2-hydroxy-ethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide(2)

A mixture of5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one(1) (1.0 g; 3.11 mmol),4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide(1.5 g; 3.57 mmol), tetrakis(triphenylphosphine)palladium (560 mg; 0.5mmol), 1N sodium carbonate (8 mL), and 1,2-dimethoxyethane (40 mL) washeated at 95° C. in a sealed pressure vessel for 16 hr. The mixture wascooled to room temperature, treated with water (70 mL) and extractedwith ethyl acetate (3×60 mL). The combined organic extracts were washedwith water (2×40 mL) and brine (1×40 mL), dried over solid sodiumsulfate, and evaporated under reduced pressure. The resulting residuewas chromatographed on silica using methanol/CH₂Cl₂ (1:9) as eluent toprovide 1.2 g of5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one(2) as a light tan solid. MS 511.23 (M+H).

Methanesulfonic acid2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethylester (3)

A solution of5-bromo-3-[4-(2-hydroxy-ethyl)-phenylamino]-1-methyl-1H-pyrazin-2-one(2) (1.2 g; 2.35 mmol) in CH₂Cl₂ (30 mL) was cooled to 0° C. and 1.5 mLof diisopropylethyl amine was added. A second solution containing 0.75mL mesyl chloride in 3 mL CH₂Cl₂ was added dropwise to the stirringreaction solution under N₂ and the reaction allowed to warm to rt for 1hr. 0.1N Sodium hydroxide was then added carefully to the reaction, andthe layers separated. The CH₂Cl₂ layer was washed with brine and driedover solid sodium sulfate, then filtered and evaporated to a lightred-brown oil (1.5 g). The crude methanesulfonic acid2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethylester (3) was used directly in subsequent reactions.

4-tert-Butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[2-(tetrahydro-pyran-4-ylamino)-ethyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide(4)

Methanesulfonic acid2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethylester (3) (0.2 g; 0.34 mmol) was dissolved in acetonitrile (2 mL) andexcess 4-aminotetrahydropyran (0.25 mL) was added. The reaction vesselwas sealed and heated to 90° C. for 4 hr. Water (10 mL) was added to thereaction vessel and the reaction was extracted with EtOAc (3×25 mL). TheEtOAc layers were pooled, washed with brine, dried over solid sodiumsulfate and filtered. The filtrate was then adsorbed directly ontosilica and chromatographed using methanol/CH₂Cl₂ (1:9) as eluent toprovide 75 mg of4-tert-butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[2-(tetrahydro-pyran-4-ylamino)-ethyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide(4) as a light tan solid. MS 594.33 (M+H).

EXAMPLE 4

The following compounds were prepared using procedures similar to thosedescribed in Examples 3A-E. Name MS Structure MW m/z

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-benzoic acid 510.23511.46

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 579.28 590.52

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-benzoic acid ethyl ester538.26 539.46

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 592.3 593.35

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 606.33 607.35

4-tert-Butyl-N-(3-{4-methyl-6-[4- (2-hydroxyethyl-methyl-carbamoyl)-phenylaminoj-S-oxo- 4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 567.28 568.48

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-benzamide 509.24 510.38

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-ethyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-benzoic acid 524.24 525.44

4-tert-Butyl-N-(3-{4-ethyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-benzamide 593.30 594.51

4-tert-Butyl-N-(3-{4-ethyl-6-[4-(4- methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-benzamide 606.33 607.36

4-tert-Butyl-N-(2-methyl-3-{4- ethyl-6-[4-(N-methylethanolamine-2-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 581.30 582.46

4-tert-Butyl-N-(3-{4-ethyl-6-[4- (methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-benzamide 537.27 538.48

4-tert-Butyl-N-{3-[6-(4-fluoro- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-benzamide 484.23 485.42

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4,5-dimethyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-benzoic acid 524.61525.42

4-{6-[3-(4-tert-Butyl- benzoylanuno)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-2-fluoro- benzoic acid528.57 529.44

4-tert-Butyl-N-(3-{3,4-dimethyl-6- [4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-benzamide 537.65 538.45

4-tert-Butyl-N-(3-{3,4-dimethyl-6- [4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-benzamide 593.72 594.47

4-tert-Butyl-N-(3-{3,4-dimethyl-6- [4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 606.76 607.41

4-tert-Butyl-N-(3-{3,4-dimethyl-6- [4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 581.70 582.45

4-tert-Butyl-N-{3-[6-(1H-indazol- 6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-benzamide 506.60 507.47

4-tert-Butyl-N-{3-[6-(1H-indazol- 5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-benzamide 506.60 507.43

4-tert-Butyl-N-(2-fluoro-3-{4- methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 583.65 584.47

4-tert-Butyl-N-(2-fluoro-3-{4- methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 596.69 597.29

4-tert-Butyl-N-(3-{6-[3-fluoro-4- (morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 597.68 598.45

4-tert-Butyl-N-(2-fluoro-3-{6-[4- (1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-benzamide 536.60537.35

4-tert-Butyl-N-{3-[6-(4- methanesulfonylaminocarbonyl-phenylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 587.69 588.52

4-tert-Butyl-N-(3-{4-methyl-6-[4- (3-aminopropyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-benzamide 566.69 567.40

4-tert-Butyl-N-(3-{6-[4-(1H- imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)- benzamide532.64 533.36

4-tert-Butyl-N-(2-methyl-3-{4- methyl-5-oxo-6-[4-(thiomorpholine-4-carbonyl)- phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 595.76 596.49

4-tert-Butyl-N-(2-methyl-3-{4- methyl-5-oxo-6-[4-(1-oxo-114-thiomorpholine-4-carbonyl)- phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 611.75 612.49

4-tert-Butyl-N-(3-{6-[4-(1,1- dioxo-116-tbiomorpholine-4-carbonyl)-phenylamino]-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 627.75 628.45

4-tert-Butyl-N-{2-methyl-3-[4- methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro- pyrazin-2-yl]-phenyl}-benzamide 545.21 546.40

4-tert-Butyl-N-{2-fluoro-3-[4- methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro- pyrazin-2-yl]-phenyl}-benzamide 549.18 550.39

4-tert-Butyl-N-(2-fluoro-3-{4- methyl-5-oxo-6-[4-(1H-tetrazol-5 -yl)-phenylamino]-4,5-dihydro- pyrazm-2-yl}-phenyl)-benzamide 538.22539.38

6-tert-Butyl-N-(3-{6-[4- (carbamoylmethyl- methyl-carbamoyl)-phenylamino]-4- pyrazin-2-yl}-2-methyl-phenyl)- nicotinamide581.28 582.29

6-tert-Butyl-N-{3-[6-(4- hydroxycarbamoyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl]-2-methyl-phenyl}- nicotinamide526.23 505.21

5-tert-Butyl-pyridine-2-carboxylic acid (3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 579.33 580.32

N-(3-{6-[4-(4-Amino-piperidin-1- yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2- methyl-phenyl)-4-tert-butyl- benzamide564.32 565.31

4-{6-[3-(4-(1-piperidinyl)- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}- benzohydroxamic acid552.25 531.26

5-tert-Butyl-pyridine-2-carboxylic acid (3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)- phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl- 600.25 601.23

5-tert-Butyl-pyrazine-2-carboxylic acid (2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide 594.31 595.27

5-tert-Butyl-pyridine-2-carboxylic acid (3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)- phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl- phenyl)-amide 594.30 595.26

N-(2-Methyl-3-{4-methyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-4-(4-methyl-piperidin-1-yl)-benzamide 620.31 621.30

4-tert-Butyl-N-{2-methyl-3-[4- methyl-6 -(5-methyl-1H-pyrazol-3-ylamino)-5-oxo-4,5-dihydro- pyrazin-2-yl]-phenyl}-benzamide 470.24471.13

5-tert-Butyl-pyridine-2-carboxylic acid (3-{6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-(pyrazin-2-yl}-2-methyl-phenyl)- amide 582.30 583.24

N-(2-Methyl-3-{4-methyl-5-oxo- 6-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-4,5- dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide 619.29 620.28

4-(1-Piperidinyl)-N-(3-{4-methyl- 6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 594.29 595.26

4-tert-Butyl-N-{2-methyl-3-[4- methyl-5-oxo-6-(1H-pyrazol-3-ylamino)-4,5-dihydro-pyrazin-2- yl]-phenyl}-benzamide 456.23 457.10

N-(3-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl)- isonicotinamide586.27 587.24

5-tert-Butyl-pyrazine-2-carboxylic acid (3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)- phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl- phenyl)-amide 601.25 602.22

Tetrahydro-furan-2-carboxylic acid (3-{6-[3-(4-tert-butyl-benzoylamino)-2-fluoro-phenyl]- 4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 583.25 585.12

5-tert-Butyl-pyridine-2-carboxylic acid (3-{6-[4-(carbamoylmethyl-methyl-carbamoyl)-phenylamino]- 4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)- amide 581.27 583.12

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[4-(carbamoylmethyl- methyl-carbamoyl)-phenylanuno]-4-methyl-5-oxo-4,5-dihydro- amide 584.22 585.22

N-(2-Methyl-3-{4-methyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-4-(3-methyl-piperidin-1-yl)-benzamide 620.31 621.30

N-{3-[6-(3-Acetylamino- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-tert-butyl-benzamide 523.26524.20

Tetrahydro-furan-3-carboxylic acid (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]- 4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 579.28 580.30

Thiazole-4-carboxylic acid (3-{6- [3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo- 3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 592.22 593.26

(3-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl)- carbamic acidethyl ester 553.27 554.25

4-tert-Butyl-N-(3-{6-[3-(2- methoxy-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 553.27 554.26

5-tert-Butyl-pyrimidine-2- carboxylic acid (2-methyl-3-(4-methyl-6-[4-(morpholine-4- carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}- phenyl)-amide 581.27 582.28

4-(Isopropyl-methyl-amino)-N-(2- methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 594.29 595.30

4-tert-Butyl-N-(2-methyl-3-{6-[4- (morpholine-4-carbonyl)-phenylaminol-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-benzamide 565.27566.31

4-tert-Butyl-N-(3-{6-[4-(1,1- dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenylamino]-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 613.27 614.33

N-[2-Methyl-3-(4-methyl-5-oxo-6- {4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5- dihydro-pyrazin-2-yl)-phenyl]-4-piperidin-1-yl-benzamide 606.33 607.38

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 578.33 579.33

4-tert-Butyl-N-(3-{6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 592.35 593.36

4-tert-Butyl-N-{3-[6-(4-{[(2- hydroxy-ethyl)-methyl-amino]-methyl}-phenylamino)-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 553.30 554.29

N-[3-(6-{4-[4-(2-Hydroxy-ethyl)- piperazine-1-carbonyl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-piperidin-1-yl- benzamide 649.34 650.40

1-(4-{4-Methyl-6-[2-methyl-3-(4- piperidin-1-yl-benzoylamino)-phenyl]-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl)-piperidine-4-carboxylic acid amide 619.32 620.36

5-tert-Butyl-pyrazine-2-carboxylic acid (3-{6-[4-(4-amino-piperidin-1-yl)-phenylamino]-4-methyl-5- oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 566.31 567.34

N-(2-Methyl-3-{4-methyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)- benzamide 635.32 636.36

4-tert-Butyl-N-[2-fluoro-3-(4- methyl-6-{3-[2-(4-methyl-piperazin-1-yl)-acetylamino]- phenylamino}-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide 625.31 626.33

N-{3-[6-(3-Amino-phenylamino)- 4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-fluoro-phenyl}-4- tert-butyl-benzamide 485.22 486.15

N-{3-[6-(3-Amino-phenylamino)- 5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl- benzamide 467.23 468.97

5-tert-Butyl-pyridine-2-carboxylic acid (2-methyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)- phenylamino]4,5-dihydro-pyrazin-2-yl}-phenyl)-amide 579.30 581.18

Tetrahydro-furan-2-carboxylic acid (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]- 3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 565.27 567.16

Tetrahydro-furan-2-carboxylic acid [3-(6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2- carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)- phenyl]-amide 569.21 571.10

Tetrahydro-furan-2-carboxylic acid (5-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]- 4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-fluoro- phenyl)-amide 597.27 599.21

Acetic acid 3-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl ester 524.24525.20

N-(2-Methyl-3-{6-[4-(morpholine- 4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}- phenyl)-4-piperidin-1-yl- benzamide 592.28593.25

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[4-(morpholin-2-ylmethoxy)-phenylaminol-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 581.3 582.33

6-tert-Butyl-pyridazine-3- carboxylic acid (2-methyl-3-{4-methyl-6-[4-(morpholine-4- carbonyl)-phenylaminoj-5-oxo- phenyl)-amide4,5-dihydro-pyrazin-2-yl}- 581.27 582.26

4-tert-Butyl-N-{2-methyl-3-[4- methyl-5-oxo-6-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6- ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide 537.23 538.18

4-Imidazol-1-yl-N-(2-methyl-3- {4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 589.24 589.29

4-tert-Butyl-N-(3-{6-[3-(3- methoxy-propionylamino)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 567.28 567.34

Furan-2-carboxylic acid (3-{6-[3- (4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo- 3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 575.25 575.33

6-tert-Butyl-N-(3-{6-[4-(1,1- dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide 586.23 587.22

4-tert-Butyl-N-[3-(6-{4-[2-(4- ethyl-piperazin-1-yl)-ethoxy]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 622.36 622.39

(3-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl)- carbamic acidtetrahydro-furan-3- yl ester 595.28 595.34

Tetrahydro-furan-2-carboxylic acid (3-{6-[3-(4-tert-butyl-benzoylarnino)-2-methyl-phenyl]- 4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 579.28 579.36

Tetrahydro-furan-2-carboxylic acid (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]- 4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 579.28 579.37

N-{3-[6-(5-Amino-pyridin-3- ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-tert-butyl-benzamide 482.24483.25

4-tert-Butyl-N-{3-[6-(1H-indol-5- ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}- benzamide 491.23 492.21

Pyrrolidine-2-carboxylic acid (3- {6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyll-4-methyl-3-oxo- 3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 578.30 579.37

4-tert-Butyl-N-(3-{6-[3-(2- hydroxy-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 539.25 539.36

4-tert-Butyl-N-[3-(6- cyclopropylamino-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2- methyl-phenyl]-benzamide 430.23 431.21

4-tert-Butyl-N-[3-(6-hydroxy-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]- benzamide 391.19 392.15

4-tert-Butyl-N-(3-{6-[3-(2-ethoxy- acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)- benzamide567.28 567.29

N-{3-[6-(3-Amino-4-methyl- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-tert-butyl-benzamide 495.26495.39

4-tert-Butyl-N-(3-{6-[4-(4- hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 579.32 580.29

4-tert-Butyl-N-(3-{6-[3-(2- hydroxy-2-methyl-propionylamino)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)- benzamide 567.28 568.30

Tetrahydro-pyran-4-carboxylic acid (3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]- 4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 593.3 594.36

4-tert-Butyl-N-{2-methyl-3-[4- methyl-5-oxo-6-(4-thiomorpholin-4-ylmethyl-phenylamino)-4,5- dihydro-pyrazin-2-yl]-phenyl}- benzamide581.28 582.32

4-(4-Hydroxy-piperidin-1-yl)-N- (2-methyl-3-{4-methyl-6-[4-(morpholme-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 622.29 623.33

N-{3-[6-(3-Amino-4-chloro- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl]-4-tert-butyl-benzamide 515.21515.32

N-(3-{6-[3-Amino-4-(morpholine- 4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 594.29 595.32

N-(2-Methyl-3-{4-methyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-4-(2-methyl-piperidin-1-yl)-benzamide 620.31 621.41

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[4-(1,1-dioxo-1λ⁶- thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 603.19 604.15

4-tert-Butyl-N-{3-[6-(3- dimethyiamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl]-2-methyl-phenyl}- benzamide509.28 510.30

4-tert-Butyl-N-(2-methyl-3-{4- methyl-5-oxo-6-[4-(piperidin-4-ylmethoxy)-phenylamino]-4,5- dihydro-pyrazin-2-yl}-phenyl)- benzamide579.32 580.32

4-tert-Butyl-N-[3-(6-{4-[(2- hydroxy-ethylamino)-methyl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 539.29 540.19

(3-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl)- carbamic acidphenyl ester 601.26 602.29

4-tert-Butyl-N-{3-[6-(4- cyclopropylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 535.29 536.28

4-tert-Butyl-N-[3-(6-{4- [(carbamoylmethyl-amino)-methyl]-phenylamino}A-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 552.28 553.31

4-(4-Methoxymethoxy-piperidin- 1-yl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 666.31 666.29

N-(3-{6-[3-(2-Amino- acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 538.26 539.38

Azetidine-2-carboxylic acid (3-{6- [3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo- 3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide 564.28 656.37

Tetrahydro-furan-2-carboxylic acid (5-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]- 4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methyl- phenyl)-amide 593.3 594.29

4-tert-Butyl-N-(3-{6-[4-(4- hydroxy-4-methyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 579.32 580.31

1-Methyl-3-[4-(morpholine-4- carbonyl)-phenylamino]-5-(2-phenyl-benzooxazol-7-yl)-1H- pyrazin-2-one 507.19 508.15

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[4-(1-methyl-piperidin-2-ylmethoxy)-phenylamino]-5- oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 593.33 594.38

5-[2-(4-Methoxy-phenyl)- benzooxazol-7-yl]-1-methyl-3-[4-(morpholine-4-carbonyl)- phenylamino]-1H-pyrazin-2-one 537.20 538.18

4-tert-Butyl-N-{3-[6-(1H-indol-5- ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-benzamide 505.24 506.17

N-{3-{6-(3-Aminomethyl- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-tert-butyl-benzamide 495.26496.19

4-tert-Butyl-N-(3-{6-[4-(1-ethyl- piperidin-4-ylmethoxy)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 607.35 608.37

4-tert-Butyl-N-{2-methyl-3-[4- methyl-5-oxo-6-(1-pyridin-4-ylmethyl-1H-mdol-6-ylamino)- 4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide 596.29 597.28

4-Furan-2-yl-N-(2-methyl-3-{4- methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 589.23 590.25

4-(2-Methoxy-1,1-dimethyl-ethyl)- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-benzamide 609.29610.31

4-tert-Butyl-N-(3-{6-[4-(4- hydroxy-4-methyl-piperidine-1-carbonyl)-phenylaminol-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 607.31 608.33

4-tert-Butyl-N-(3-{6-[4-(4- hydroxy-4-methyl-piperidin-1-ylmethyl)-phenylamino]-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 593.33 594.38

6-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid{3-[6-(3-amino- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-amide 499.20 500.13

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-2-hydroxy- benzoic acid526.22 527.19

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[4-(morpholine-4-carbonyl)-3-nitro-phenylamino]-5- oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 624.26 625.32

5-Ethyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-amide 611.25612.28

4-Azetidin-1-yl-N-(2-methyl-3-{4- methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 578.26 579.27

4-tert-Butyl-3-methoxy-N-(2- methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 609.29 610.31

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-2-methoxy- benzoic acid540.23 541.20

1,4,4-Trimethyl-1,2,3,4- tetrahydro-quinoline-7-carboxylic acid(2-methyl-3-{4-methyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-amide 620.31621.32

4-(1-Methoxy-1-methyl-ethyl)-N- (2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)- phenylan-iino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 595.28 496.19

4-(2,2-Dimethyl-propionyl)-N-(2- methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 607.28 608.30

4-tert-Butyl-N-(3-{6-[3-methoxy- 4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 609.29 610.33

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-2-methoxy-N-(3-methoxy-propyl)-benzamide 611.31 612.31

N-{3-[6-(3-Acryloylamino- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-tert-butyl-benzamide 535.26536.20

4-tert-Butyl-N-{3-[6 -(1H-indol-4- ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-benzamide 505.24 506.23

4-tert-Butyl-N-[3-(6-{4-[(2- methoxy-ethylamino)-methyl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 553.30 554.27

4-tert-Butyl-N-{3-[6-(4- ethylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl]-2-methyl-phenyl}- benzamide523.29 524.26

4-tert-Butyl-N-{3-[6-(4- diethylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 551.32 552.30

4-tert-Butyl-N-[3-(6-{4- [(isopropyl-methyl-amino)-methyl]-phenylamino}-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 551.32 552.26

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[4-(2-methyl-piperidin-1-ylmethyl)-phenylaminol-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 577.34 578.32

4-tert-Butyl-N-[2-methyl-3-(4- methyl-5-oxo-6-{4-[2-{tetrahydro-pyran-4-ylamino)-ethyl]- phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide 593.33 594.33

5-Amino-2-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-N- cyclopropyl-benzamide564.28 565.27

5-Amino-benzo[b]thiophene-2- carboxylic acid (2-methyl-3-{4-methyl-6-[4-(morpholine-4- carbonyl)-phenylaminol-5-oxo-4,5-dihydro-pyrazin-2-yl}- phenyl)-amide 594.20 595.19

2-Amino-N-{3-[6-(benzothiazol-6- ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-piperidin-1-yl- benzamide565.22 566.21

4-tert-Butyl-N-[3-(6-{2-[(2- hydroxy-ethyl)-methyl-amino]-pyridin-4-ylamino}-4-methyl-5- oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 540.28 541.23

4-tert-Butyl-N-(3-{6-[3-methoxy- 4-(4-methyl-piperazine-1-carbonyi)-phenylamino]-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 622.32 623.33

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-N-(2-hydroxy-ethyl)-2-methoxy-N- methyl-benzamide 597.29 598.32

4-tert-Butyl-N-(3-{6-[3-methoxy- 4-(piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 607.31 608.32

N-{3-[6-(3-Amino-4-morpholin-4- yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2- methyl-phenyl}-4-tert-butyl- benzamide566.30 567.10

N-{3-[6-(4-Amino-2-piperidin-1- ylmethyl-phenylamino) -4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]- 2-methyl-phenyl}-4-tert-butyl-benzamide 578.33 579.38

(4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-benzylamino)- acetic acid553.26 576.28

4-tert-Butyl-N-[3-(6-{4- [(cyclopropylmethyl-amino)-methyl]-phenylamino}-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 549.31 550.31

N-{3-[6-(3-Amino-4- thiomorpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide 582.27 583.37

4-tert-Butyl-N-(2-methyl-3-{4- methyl-5-oxo-6-[4-(piperidin-3-ylmethoxy)-phenylamino]-4,5- dihydro-pyrazin-2-yl}-phenyl)- benzamide579.32 580.45

N-(3-{6-[3-Amino-4-(1,1-dioxo- 1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 614.26 615.33

N-(3-{6-[3-Amino-4-(piperidine- 1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 592.31 593.36

4-tert-Butyl-N-{2-methyl-3-[4- methyl-5-oxo-6-(1,2,3,4-tetrahydro-isoquinolin-6-ylamino)- 4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide 521.28 522.25

4-tert-Butyl-N-[3-(6-{4-[2-(4- ethyl-piperazin-1-yl)-ethyl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 606.36 607.42

4-tert-Butyl-N-[3-(6-{4-[2-(2- hydroxy-ethylamino)-ethyl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 553.30 554.30

4-tert-Butyl-N-{3-[6-(4-{2-[(2- hydroxy-ethyl)-methyl-amino]-ethyl}-phenylamino)-4-methyl-5- oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 567.32 568.33

4-tert-Butyl-N-(3-{6-[4-(2- diethylamino-ethyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide 565.34 566.34

2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyll-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-N-(2-hydroxy-ethyl)-N-methyl- 582.29 583.30

4-[2-(2-Methoxy-ethoxy)-1,1- dimethyl-ethyl]-N-(2-methyl-3-(4-methyl-6-[4-(morpholine-4- carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}- phenyl)-benzamide 653.32 654.40

4-(3-Methoxymethoxy-piperidin- 1-yl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 666.31 667.57

4-tert-Butyl-N-{3-[6-(4- hydroxymethyl-3-methoxy-phenylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 526.25 527.23

4-tert-Butyl-N-{3-[6.{1H-indol-6- ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-benzamide 505.24 506.19

N-(3-{6-[3-Amino-4-(4-methyl- piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 607.32 608.38

N-(3-{6-[3-Amino-4-(4-ethyl- piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 621.34 622.35

2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-N-(2-dimethylamino-ethyl)-benzamide 595.32 596.31

4-tert-Butyl-N-{2-methyl-3-[6-(4- morpholin-4-yl-3-nitro-phenylamino)-5-oxo-4,5-dihydro- pyrazin-2-yl]-phenyl}-benzamide 582.26583.32

4-tert-Butyl-N-{2-methyl-3-[4- methyl-6-(4-morpholin-4-yl-3-nitro-phenylamino)-5-oxo-4,5- dihydro-pyrazin-2-yl]-phenyl}- benzamide596.27 597.28

N-{3-[6-(3-Amino-4-morpholin-4- yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-tert-butyl-benzamide 552.28553.19

2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-N-(2-diethylamino-ethyl)-benzamide 623.36 624.34

4-tert-Butyl-N-(3-{4-ethyl-6-[4- (phenyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-benzamide 585.27 586.29

4-tert-Butyl-N-(3-{4-ethyl-6-[4-(2- methyl-phenyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-benzamide 599.29 600.33

4-tert-Butyl-N-(3-[6-(4- cyclopropylaminomethyl-3-methoxy-phenylamino)-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 565.30 566.26

4-tert-Butyl-N-{3-[6-(4- cyclopropylaminomethyl-3- methoxy-phenylamino)-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl]- 2-methyl-phenyl}-benzamide642.26 643.49

4-tert-Butyl-N-{3-[6-(3-{2-[(2- hydroxy-ethyl)-methyl-amino]-ethyl}-phenylamino)-4-methyl-5- oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 567.32 568.33

N-(3-{6-[3-Amino-4-(1-oxo-1λ⁴- thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 626.26 627.50

4-(1-Methyl-cyclobutyl)-N-(2- methyl-3-{4-methyl-6-[4-phenylamino]-5-oxo-4,5-dihydro- (morpholine-4-carbonyl)-pyrazin-2-yl}-phenyl)-benzamide 591.28 592.33

N-{3-[6-(4-{[Bis-(2-hydroxy- ethyl)-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl]-2-methyl-phenyl)-4-tert-butyl-benzamide 583.31 584.24

4-tert-Butyl-N-[3-(6-{3-[2-(2- hydroxy-ethylamino)-ethyl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 553.30 554.19

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[3-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-4,5- dihydro-pyrazin-2-yl}-phenyl)- benzamide579.32 580.20

4-tert-Butyl-N-[3-(6-{3-[2-(1,1- dioxo-1λ⁶-thiomorpholin-4-yl)-ethyl]-phenylamino}-4-methyl-5- oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 627.28 628.25

4-tert-Butyl-N-[3-(6-{3-[2-(4- ethyl-piperazin-1-yl)-ethyl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide 606.36 607.28

N-{3-[6-(3-{2-[Bis-(2-hydroxy- ethyl)-amino]-ethyl}-phenylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide 597.33 598.25

4-tert-Butyl-N-{3-[6-(3,4-dihydro- 2H-benzo[1,4]oxazin-6-ylamino)-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl]-2-methyl-phenyl}- benzamide523.25 524.10

N-(3-{6-[4-(4-Aminomethyl-4- hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 594.33 595.38

2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-benzoic acid 525.23526.28

5-(3-Amino-2-methyl-phenyl)-1- methyl-3-(4-morpholin-4-yl-3-nitro-phenylamino)-1H-pyrazin-2- one 436.18 437.20

5-tert-Butyl-pyridine-2-carboxylic acid {3-[6-(3-amino-4-morpholin-4-yl-phenylamino)-4-methyl-5- oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide 567.29 568.21

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid{3-[6-(3-amino-4-morpholin- 4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2- methyl-phenyl}-amide 570.24 571.31

N-{3-[6-(3-Arnino-4-morpholin-4- yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2- methyl-phenyl}-4-piperidin-1-yl- benzamide593.31 594.26

N-(2-Methyl-3-{4-methyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-4-methylsulfanyl-benzamide 569.21 570.15

N-{3-[6-(3-Amino-4- cyclopropylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide 551.41 550.30

5-Methyl-4,5,6,7-tetrahydro- acid (3-{6-[3-amino-4-benzo[b]thiophene-2-carboxylic (morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 612.25 613.21

N-(3-{6-[3-Amino-4- (thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- phenyl)-4-tert-butyl-benzamidedihydro-pyrazin-2-yl}-2-methyl- 610.27 611.44

2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-N-pyridin-3- yl-benzamide601.28 602.36

N-(5-{6-[3-Amino-4-(morpholine- 4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 594.29 595.46

2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-N-(2-methoxy-ethyl)-N-methyl- benzamide 596.31 597.37

Octahydro-isoquinoline-2- carboxylic acid (2-methyl-3-{4-methyl-6-[4-(morpholine-4- carbonyl)-phenylamino]-5 -oxo-4,5-dihydro-pyrazin-2-yl}- phenyl)-amide 584.31 585.29

N-(3-{6-[3-Amino-4-(morpholine- 4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-6-tert-butyl-nicotinamide 595.29 596.40

N-{3-[6-(2-Amino-indan-5- ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-tert-butyl-benzamide 521.28522.26

N-(3-{6-[3-Amino-4-(morpholine- 4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-fluoro-phenyl)-4-tert-butyl-benzamide 598.27 599.43

N-{3-[6-(3-Amino-4-methoxy- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-4-tert-butyl-benzamide 511.25512.34

N-(3-{6-[3-Amino-4-(1-oxo-1λ⁴- thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 598.27 599.38

N-(3-{6-[3-Amino-4-(4-hydroxy- piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 580.31 581.35

N-(3-{6-[3-Amino-4-(4-ethyl- piperazin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 607.3632 608.53

1-(2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl)-piperidine-4-carboxylic acid amide 607.32 608.43

N-{3-[6-(3-Amino-4-morpholin-4- yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2- fluoro-phenyl}-4-tert-butyl- benzamide570.27 571.39

N-(3-{6-[3-Amino-4-(4-ethyl- piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 593.34 594.39

N-(3-{6-[4-(4-Aminomethyl-4- hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 622.32 623.70

N-(3-{6-[4-(1,1-Dioxo-1λ⁶- thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-pentafluoroethyl- benzamide 661.17 662.32

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid{2-methyl-3-[4-methyl-6-(4- morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro- pyrazin-2-yl]-phenyl}-amide 583.26584.28

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4- (morpholine-4-carbonyl)-phenylaminoj-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-fluoro--phenyl)-amide 616.22 617.39

N-{3-[6-(3-Amino-4- [1,4]oxazepan-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide 580.31 581.32

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-hydroxy- piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)- amide 598.27600.30

N-[3-(6-{3-Amino-4-[4-(2- hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl- 609.34 611.40

4-tert-Butyl-N-{3-[6-(3-methoxy- 4-morpholin-4-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 595.31 596.21

N-(3-{6-[3-Amino-4-(4-hydroxy- 4-methyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 594.33 596.31

N-(3-{6-[3-Amino-4-(2- morpholin-4-yl-ethoxy)-phenylamino]A-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 610.32 612.40

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4- (morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 598.23 599.10

N-[3-(6-{3-Amino-4-[(2-methoxy- ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl- benzamide 568.31 569.21

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-2-methyl- benzoic acidmethyl ester 538.25 539.36

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-2-methyl- benzoic acid524.24 525.33

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4- (morpholme-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-amide 602.21 604.31

4-tert-Butyl-N-{2-methyl-3-[4- methyl-6-(3-methyl-4-morpholin-4-yl-phenylamino)-5-oxo-4,5- dihydro-pyrazin-2-yl]-phenyl}- benzamide565.30 566.33

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4- (4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-amide 596.26597.20

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4-methyl-5-oxo- 6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}- 4,5-dihydro-pyrazin-2-yl)-phenyl]- amide597.28 598.17

4-tert-Butyl-N-{2-methyl-3-[4- methyl-6-(4-[1,4]oxazepan-4-ylmethyl-phenylamino)-5-oxo-4,5- dihydro-pyrazin-2-yl]-phenyl}-benzamide 579.32 580.17

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid{3-[6-(4-hydroxymethyl- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-amide 514.20 515.23

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid[3-(6-{4-[(carbamoylmethyl- amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl)-2-methyl-phenyl]- amide 570.24571.20

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4- (morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)- amide598.23 599.24

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-hydroxy- piperichn-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)- amide 584.26585.17

1-(2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl)-4-hydroxy-pyridinium 575.28 575.23

N-[3-(6-{3-Amino-4-[(2-hydroxy- ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2- benzamide554.30 555.18

N-(3-{6-[3-Amino-4-(morpholine- 4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2- methyl-phenyl)-4-piperidin-1-yl- benzamide607.29 608.22

N-(3-{6-[3-Amino-4-(4-methyl- piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 579.33 580.24

5,6,7,8-Tetrahydro-naphthalene-2- carboxylic acid (2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴- thiomorpholm-4-yl)-phenylamino]-4,5-dihydro- pyrazin-2-yl}-phenyl)-amide 581.25 582.25

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4- (4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl}-phenyl)-amide 596.26597.21

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4-methyl-5-oxo- 6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}- 4,5-dihydro-pyrazin-2-yl)-phenyl]- amide597.28 598.17

4-tert-Butyl-N-{2-methyl-3-[4- methyl-6-(4-[1,4]oxazepan-4-ylmethyl-phenylamino)-5-oxo-4,5- dihydro-pyrazin-2-yl]-phenyl}-benzamide 579.32 580.17

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid{3-[6-(4-hydroxymethyl- phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl- phenyl}-amide 514.20 515.23

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid[3-(6-{4-[(carbamoylmethyl- amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl)-2-methyl-phenyl]- amide 570.24571.20

5-Methyl-4,5,6,7-tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4- (morpholine-4-carbonyl)-phenylanuno]-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)- amide598.24 599.23

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-hydroxy- piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)- amide 584.26585.16

1-(2-Amino-4-{6-[3-(4-tert-butyl- benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino}-phenyl)-4-hydroxy-pyridinium 575.28 575.23

N-[3-(6-{3-Amino-4-[(2-hydroxy- ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo- methyl-phenyl]-4-tert-butyl- benzamide554.30 555.25

N-(3-{6-[3-Amino-4-(morpholine- 4-carbonyl)-phenylamino]-5 -oxo-4,5-dihydro-pyrazine-2-yl}-2- methyl-phenyl)-4-piperidine-1-yl-benzamide 607.29 608.13

N-(3-{6-[3-Amino-4-(4-methyl- piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 579.33 580.26

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-hydroxy- piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 612.25 613.18

N-(3-{6-[3-Amino-4-(3-hydroxy- piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 580.32 581.23

N-(3-{6-[3-Amino-4-(3-hydroxy- pyrrolidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 566.30 567.23

N-{3-[6-(3-Amino-4-piperidin-1- yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2- methyl-phenyl}-4-tert-butyl- benzamide564.32 565.23

4-(2-Hydroxy-1,1-dimethyl-ethyl)- N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide 595.28 596.19

1-[2-Amino-4-(4-methyl-6-{2- methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)- amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)- benzoyl]-pipericline-4-carboxylic acid amide639.26 640.18

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(3-hydroxy- pyrrolidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 598.24 599.18

4,5,6,7-Tetrahydro- benzo[b]tbiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-ethyl- piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 625.28 626.19

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(3-hydroxy- piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 612.25 613.17

N-(3-{6-[3-Amino-4-(4-methyl- [1,4]diazepan-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 593.35 594.25

N-(3-{6-[3-Amino-4-(2- hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 596.31 597.22

N-(3-{6-[3-Amino-4-(4- hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 594.33 595.30

1-[2-Amino-4-(4-methyl-6-{2- methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)- amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)- phenyl]-piperidine-4-carboxylic 611.26612.16

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(2- hydroxymethyl-morpholin-4-yl)-phenylanuno]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide 600.25 601.15

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid[3-(6-{3-amino-4-[(2- hydroxy-ethyl)-methyl- carbamoyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl)-2-methyl-phenyl]- amide 586.24587.20

4-tert-Butyl-N-(2-methyl-3-{4- methyl-6-[3-nitro-4-(pyridin-3-yloxy)-phenylamino]-5-oxo-4,5- dihydro-pyrazin-2-yl}-phenyl)- benzamide604.24 605.26

N-[3-(6-{3-Amino-4-[4-(2- hydroxy-ethyl)-piperidin-1-yl]-phenylamino}-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl- benzamide 608.35 609.26

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid{2-methyl-3-[4-methyl-5-oxo- 6-(pyridin-3-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}- amide 471.17 472.13

4-tert-Butyl-N-{3-[6-(3-fluoro-4- morpholin-4-ylmethyl-phenylamino)-4-methyl-5-oxo-4- dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide 583.30 584.27

N-(3-{6-[3-Amino-4-(4-methoxy- piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl) -4-tert-butyl-benzamide 594.33 595.25

N-(3-{6-[3-Amino-4-(4-cyano- piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 589.32 590.23

1-[2 -Amino-4-(4-methyl-6-{2- methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)- amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)- phenyl]-piperidine-3-carboxylic acid amide611.27 612.2

N-(3-{6-[3-Amino-4-(3- hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 594.33 595.3

N-(3-{6-[3-Amino-4-(3-methyl- piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide 579.33 580.3

4,5,6,7-Tetrahydro- benzo[b]thiophene-2-carboxylic acid{2-methyl-3-[4-methyl-5-oxo- 6-(pyridin-4-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}- amide 471.17 472.07

EXAMPLE 5 Synthesis of4-tert-Butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamideStep 1: 2-(2-Methyl-3-nitrophenyl)-5,5-dimethyl[1,3,2]dioxaborinane

A mixture of 2-bromo-6-nitrotoluene (3.2 g; 14.8 mmol), bis(neopentylglycolato)diboron (4 g; 17.7 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichlropalladium, 1:1 complexwith dichloromethane (362 mg; 0.44 mmol), potassium acetate (7.3 g; 73.8mmol), and dioxane (75 mL) is heated at reflux for 3 h.

The mixture is then cooled to room temperature, treated with water (100mL), and extracted with ethyl acetate (3×80 mL). The extracts are washedwith water (2×50 mL) and brine (1×50 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue is purified by flashchromatography over silica gel (elution with hexane/EtOAc 95/5-6/1,gradient) to afford2-(2-methyl-3-nitrophenyl)-5,5-dimethyl[1,3,2]dioxaborinane as a whitesolid (3.3 g)

Step 2: 3-(5,5-Dimethyl[1,3,2]dioxaborinan-2-yl)-2-methylaniline

A mixture of 2-(2-methyl-3-nitrophenyl)-5,5-dimethyl[1,3,2]dioxaborinan(6.7 g; 27.7 mmol), 10% palladium-on-carbon (670 mg), ethyl acetate (75mL) and methanol (75 mL) is treated with 40 psi of hydrogen for 2 h atroom temperature.

The mixture is filtered through celite, washing with DCM (2×100 mL), andthe filtrate is concentrated in vacuo to afford3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2-methylaniline as a whitesolid (6.0 g)

Step 3:4-t-Butyl-N-[3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2-methylphenyl]-benzamide

A solution of 3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2-methylaniline(3.1 g; 14.2 mmol) and triethylamine (3.0 mL; 21.2 mmol) in THF (110 mL)is treated dropwise with 4-(t-butyl)benzoyl chloride (2.6 mL; 14.2 mmol)and the mixture is stirred at room temperature for 15 min.

The mixture is then filtered through Celite, and washed with EtOAc, thefiltrate is concentrated in vacuo to afford4-t-butyl-N-[3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2-methylphenyl]-benzamideas a white solid (4.0 g).

Step 4:4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methylphenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid ethyl ester

A mixture of 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acidethyl ester (687 mg; 1.9 mmol),4-t-butyl-N-[3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2-methylphenyl]-benzamide(866 mg; 2.3 mmol), palladium tetrakis(triphenylphosphine) (220 mg; 0.19mmol), 1N aqueous sodium carbonate (3 mL), and DME (13 mL) is heated at95° C. in a sealed tube for 16 h.

The mixture is then cooled to room temperature, treated with water (30mL) and extracted with ethyl acetate (3×40 mL). The extracts are washedwith brine (1×50 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue is triturated with hexane andfiltered to afford4-{6-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid ethyl ester as a dark yellow solid (600 mg).

Step 5:4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methylphenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid

A mixture of4-{6-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid ethyl ester (600 mg; 1.1 mmol), ethanol (50 mL) and 1N aqueoussodium hydroxide (50 mL) is heated at reflux for 1 h.

The mixture is then cooled to room temperature, adjusted to pH 6 with 1NHCl and extracted with ethyl actetate (3×100 ml). The extracts arewashed with brine (1×50 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue is triturated with ethyl acetate toafford4-{6-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid as a white solid (300 mg).

Step 6:4-tert-Butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide

A mixture of4-{6-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid (52 mg; 0.1 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(49 mg; 0.11 mmol), diisopropylethylamine (0.05 mL; 0.3 mmol), and DMF(1.7 mL) is stirred at room temperature for 20 min. Morpholine (0.04 mL)is added and the mixture is stirred at room temperature for 2 h.

Water (10 mL) is then added and the mixture filtered to afford4-tert-Butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamideas a white solid (40 mg).

EXAMPLE 6 Synthesis of6-tert-Butyl-N-{2-methyl-3-[8-(4-morpholin-4-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-nicotinamide

Step 1: 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid

4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid ethyl ester(10.0 g; 27.7 mmol) is dissolved in 200 mL ethanol (200 proof) and 100mL 1 N NaOH is added. The reaction is refluxed for 2 hours and thencooled to rt. The resulting solid is filtered and collected, thenslurried up in 0.1 N HCl (75 mL) and extracted with CH₂Cl₂ (2×75 mL).The pooled CH₂Cl₂ layers is washed with brine, then dried over anhydroussodium sulfate and concentrated in vacuo to provide4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid as a whitesolid (8 g).

Step 2:[4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone

A mixture of 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid(4.0 g, 12.0 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (6.0 g; 13.6 mmol), and diisopropylethylamine (6 mL;34.4 mmol) is dissolved in dimethylacetamide (50 mL) and stirred at roomtemperature for 20 min. Morpholine (5 mL; 57 mmol) is added and themixture is stirred at room temperature for 16 hr.

Water (100 mL) is added and the mixture is filtered to give[4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanoneas a cream solid (2.65 g)

Step 3:{4-[6-(3-Amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-morpholin-4-yl-methanone

A mixture of[4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone(500 mg; 1.24 mmol),3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-methyl-phenylamine (340 mg;1.6 mmol), palladium tetrakis(triphenylphosphine) (200 mg; 0.17 mmol),1M sodium carbonate (10 mL), and DME (25 mL) is heated at 950 in asealed tube for 16 hr.

The mixture is cooled to room temperature, treated with water (75 mL)and extracted with ethyl acetate (3×80 mL). The extracts are washed withwater (2×100 mL) and brine (1×100 mL), dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue is triturated with etherand filtered to give{4-[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-morpholin-4-yl-methanoneas a tan solid (540 mg).

Step 4:[6-(3-Amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(4-morpholin-4-ylmethyl-phenyl)-amine

{4-[6-(3-Amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-phenyl}-morpholin-4-yl-methanone(350 mg; 0.82 mmol) is dissolved in anhydrous THF (5 mL) under nitrogenat rt. Solid lithium aluminum hydride (0.5 g) is added portion-wise tothe stirring reaction, and the reaction refluxed under nitrogen for 2hr. The reaction is cooled to 0° C. in an ice bath and quenchedcarefully by the dropwise addition of water (0.5 mL), then 15%NaOH_((aq)) (0.5 mL), and finally by more water (5 mL). The reaction isstirred at 0° C. for 15 minutes then the slurry is filtered throughcelite to remove the aluminum salts. The filtrate is partitioned betweenwater and ethyl acetate, and the ethyl acetate layer is washed withwater (1×50 mL), and brine (1×50 mL), then dried over anhydrous sodiumsulfate and concentrated in vacuo to provide[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(4-morpholin-4-ylmethyl-phenyl)-amineas a tan solid (300 mg), which is pure enough to use in further steps.

Step 5: 6-tert-Butyl-nicotinic acid

Nicotinic acid (1.0 g; 7.3 mmol) is dissolved in a mixture of water (10mL) and conc. H₂SO₄ (0.5 mL) with stirring. tert-Butyl carboxylic acidis added, and the resulting crystalline slurry stirred under nitrogen.Catalytic AgNO₃ and ammonium persulfate (140 mg; 0.61 mmol) are thenadded, the flask wrapped in aluminum foil to shield from light and thereaction heated to 90° C. for 3 hr. The reaction is cooled to 0° C.,basified to pH 10 and extracted with EtOAc (4×50 mL). The pooled organiclayers are washed with saturated sodium carbonate (2×50 mL) and brine,dried over anhydrous sodium sulfate and concentrated in vacuo. Theresulting oil is purified by flash chromatography over silica gel toprovide 6-tert-butyl-nicotinic acid (1.1 g) as a white solid.

Step 6:6-tert-Butyl-N-{2-methyl-3-[8-(4-morpholin-4-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-nicotinamide

A mixture of[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(4-morpholin-4-ylmethyl-phenyl)-amine(150 mg; 0.36 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (450 mg; 1.0 mmol), and diisopropylethylamine (0.3mL; 1.7 mmol) is dissolved in dimethylacetamide (1 mL) and stirred atroom temperature for 20 min. 6-tert-butyl-nicotinic acid (200 mg; 1.1mmol) is added and the mixture is stirred at room temperature for 16 hr.

Water (10 mL) is added and the mixture is filtered to give6-tert-Butyl-N-{2-methyl-3-[8-(4-morpholin-4-ylmethyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-nicotinamideas a crude tan solid (120 mg). The crude solid is purified by flashchromatography over silica gel to provide the final compound as a palecream solid (100 mg)

EXAMPLE 7 Synthesis of3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenylamine

Step 1: 2-(2-Fluoro-3-nitro-phenyl)-5,5-dimethyl-[1,3,2]dioxaborinane

A mixture of 1-bromo-2-fluoro-3-nitrobenzene (800 mg; 3.63 mmol),bis(neopentyl glycolato)diboron (900 mg; 3.98 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichlropalladium, 1:1 complexwith dichloromethane (100 mg; 0.12 mmol), potassium acetate (1.0 g; 10.2mmol), and dioxane (20 mL) was heated at reflux for 16 hr.

The mixture is cooled to room temperature, treated with water (100 mL),and extracted with ethyl acetate (3×25 mL). The extracts are washed withwater (2×25 mL) and brine (1×25 mL), dried over sodium sulfate, andconcentrated in vacuo. The residue is purified by flash chromatographyover silica gel (elution with ether/hexane 1/2) to give2-(2-fluoro-3-nitro-phenyl)-5,5-dimethyl-[1,3,2]dioxaborinane as a paleyellow solid (350 mg)

Step 2: 3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenylamine

A mixture of2-(2-fluoro-3-nitro-phenyl)-5,5-dimethyl-[1,3,2]dioxaborinane (240 mg;1.1 mmol), 10% palladium-on-carbon (100 mg) and ethyl acetate (75 mL) ishydrogenated at room temperature and 40 psi hydrogen for 2 hr.

The mixture is filtered through celite, washed with CH₂Cl₂ (2×100 mL),and the filtrate is evaporated to give3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenylamine as an tansolid (200 mg)

EXAMPLE 8

The following compounds were prepared using procedures similar to thosedescribed in Examples 5-7. Structure Name MW M+

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl- phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid C₃₁H₂₉N₅O₃Mol. Wt.: 519.59 520.2

4-tert-Butyl-N-(2-methyl-3-{8- [4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamideC₃₅H₃₆N₆O₃Mol. Wt.: 588.70 589.2

4-tert-Butyl-N-(2-methyl-3-{8- [4-(4-methyl-piperazine-1-carbonyl)-phenylamino]- imidazo[1,2-a]pyrazine-6-yl}- phenyl)-benzamideC₃₆H₃₉N₇O₂Mol. Wt.: 601.74 602.3

4-tert-Butyl-N-(2-methyl-3-{8- [4-(N-methylhydroxyethyl-1-carbonyl)-phenylamino]- imidazo[1,2-a]pyrazine-6-yl}- phenyl)-benzamideC₃₄H₃₆N₆O₃Mol. Wt.: 576.69 577.1

4-tert-Butyl-N-(2-methyl-3-{8- [4-(N-methylethyl-1-carbonyl)-phenylamino]- imidazo[1,2-a]pyrazine-6-yl}- phenyl)-benzamideC₃₄H₃₆N₆O₂Mol. Wt.: 560.69 561.3

4-{6-[3-(4-tert-Butyl- benzoylamino)-2-methyl- phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoic acid ethyl ester C₃₃H₃₃N₅O₃Mol. Wt.: 547.65548.3

4-tert-Butyl-N-(2-fluoro-3-{8- [4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamideC₃₄H₃₃FN₆O₃Mol. Wt.: 592.66 593.3

4-tert-Butyl-N-(2-methyl-3-{8- [4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamideC₃₅H₃₆N₆O₃Mol. Wt.: 588.70 534.5

4-tert-Butyl-N-{2-methyl-3-[8- (4-morpholin-4-ylmethyl-phenylamino)-imidazo[1,2- a]pyrazin-6-yl]-phenyl}- benzamideC₃₅H₃₈N₆O₂Mol. Wt.: 574.72 575.3

N-(2-Methyl-3-{8-[4- (morpholine-4-carbonyl)- phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4- methylsulfanyl-benzamide C₃₂H₃₀N₆O₃S Mol.Wt.: 578.69 579.5

4-tert-Butyl-N-(2-methyl-3-{8- [4-(1H-tetrazol-5-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C₃₁H₂₉N₉OMol. Wt.: 543.62 544.2

4-tert-Butyl-N-(2-methyl-3-{8- [4-(1H-tetrazol-5-ylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C₃₂H₃₁N₉OMol. Wt.: 557.65 558.4

EXAMPLE 9

4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile

A mixture of 4-aminobenzonitrile (220 mg; 1.89 mmol) and6,8-dibromo-imidazo[1,2-a]pyrazine (500 mg; 1.81 mmol) is slurried inDMF (1 mL) and heated to 140° C. for 20 minutes. The reaction is allowedto cool, and when the bath reaches 75° C., ethyl acetate (40 mL) isadded and the slurry is stirred to break up large solid lumps into finepowder. The powdered4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile is filtered,washed with diethyl ether (2×50 mL) and dried under vacuum to a fineorange/tan solid (600 mg).

4-[6-(3-Amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrile

A solution of 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile(1.02 g; 3.27 mmol) is slurried in ethylene glycol, dimethyl ether (DME;60 mL) and nitrogen gas bubbled through the reaction for 15 minutes withstirring at rt.

3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-methyl-phenylamine (950 mg;3.63 mmol) and palladium tetrakis(triphenylphosphine) (500 mg; 0.43mmol) are added and nitrogen is bubbled through the reaction slurry foran additional 10 minutes at rt. 20 mL of a 1.0N solution of sodiumcarbonate is added and the biphasic mixture is heated to 95° C. for 16hrs with vigorous stirring under nitrogen. The mixture is partitionedbetween ethyl acetate (100 mL) and water (100 mL) and the water layerextracted with ethyl acetate (2×50 mL). The organic layers are pooled,washed with brine and dried over anhydrous sodium sulfate. The filtrateis then concentrated in vacuo and the crude oil dissolved in a minimumvolume of CH₂Cl₂. Diethyl ether is added and the resulting precipitateis filtered and washed with diethyl ether to provide4-[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrileas a pale tan solid (650 mg).

4-tert-Butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamide

A solution of4-[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrile(380 mg; 1.12 mmol) and diisopropylethylamine (187 mg; 1.45 mmol) inanhydrous THF (25 mL) is stirred under nitrogen at rt. A solution of4-tert-Butyl-benzoyl chloride (230 mg; 1.17 mmol) in 5 mL anhydrous THFis then added dropwise to the stirring reaction solution. After 30minutes, the mixture is partitioned between ethyl acetate (75 mL) andwater (75 mL) and the water layer extracted with ethyl acetate (2×50mL). The organic layers are pooled, washed with brine and dried overanhydrous sodium sulfate. The filtrate is then concentrated in vacuo andthe crude oil dissolved in a minimum volume of CH₂Cl₂. Diethyl ether isadded and the resulting precipitate is filtered and washed with diethylether to provide4-tert-butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamideas a light orange solid (450 mg)

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride

4-tert-Butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamideis slurried in 200 mL ethanol (200 proof) and the reaction cooled to 0°C. in an ice bath. The reaction is then saturated with hydrogen chloridegas and allowed to gradually warm to rt over 16 hrs with stirring. Thesolvent is removed in vacuo and the resulting tan solid4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride (500 mg) is used without furtherpurification.

4-tert-Butyl-N-(2-methyl-3-{8-[4-(N-methylcarbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride (150 mg; 0.26 mmol) is dissolved inmethanol (1 mL) in a glass pressure reaction vessel, and a solution ofmethylamine in THF added (2.0N; 2 mL). The reaction is heated to 50° C.for 2 hr then concentrated in vacuo. The oil is dissolved in 2 mL CH₂Cl₂and diethyl ether (20 mL) is added to precipitate out4-tert-butyl-N-(2-methyl-3-{8-[4-(N-methylcarbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamideas a clean light tan solid (140 mg).

4-tert-Butyl-N-(3-{8-[4-(N,N′-dimethyl-carbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamide

4-tert-Butyl-N-(2-methyl-3-{8-[4-(N-methylcarbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide(100 mg; 0.19 mmol) is dissolved in methanol (1 mL) in a glass pressurereaction vessel, and a solution of methylamine in THF is added (2.0N; 5mL). The reaction is heated to 60° C. for 16 hr then concentrated invacuo. The resulting oil is dissolved in 2 mL CH₂Cl₂ and diethyl ether(20 mL) is added to precipitate out4-tert-butyl-N-(3-{8-[4-(N,N′-dimethyl-carbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamide(80 mg). Gradient silica flash chromatography using (90:9:1)(CH₂Cl₂:methanol:ammonium hydroxide) as the eluent provides the purematerial as a white solid (60 mg).

Alternatively,4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride (150 mg; 0.26 mmol) is dissolved inmethanol (1 mL) in a glass pressure reaction vessel, and a solution ofmethylamine in THF added (2.0N; 5 mL). The reaction is heated to 60° C.for 16 hr then concentrated in vacuo. The oil is dissolved in 2 mLCH₂Cl₂ and diethyl ether (20 mL) is added to precipitate out4-tert-butyl-N-(3-{8-[4-(N,N′-dimethyl-carbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamideas a light tan solid (100 mg). Gradient silica flash chromatographyusing (90:9:1) (CH₂Cl₂:methanol:ammonium hydroxide) as the eluentprovides the pure material as a white solid (50 mg).

4-tert-Butyl-N-(3-{8-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamide

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride (150 mg; 0.26 mmol) is dissolved inmethanol (5 mL) in a glass pressure reaction vessel, and ethylenediamine(100 mg; excess) is added. The reaction is heated to 60° C. for 16 hrthen concentrated in vacuo. The oil is dissolved in 2 mL CH₂Cl₂ anddiethyl ether (20 mL) is added to precipitate out4-tert-butyl-N-(3-{8-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamideas a light tan solid (100 mg). Gradient silica flash chromatographyusing (90:9:1) (CH₂Cl₂:methanol:ammonium hydroxide) as the eluentprovides the pure material as a white solid (50 mg).

EXAMPLE 10

The following compounds were prepared using procedures similar to thosedescribed in Example 9 above. Structure Name MW M+

4-tert-Butyl-N-(3-{8-[4-(2- imino-2-morpholin-4-yl- ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- 2-methyl-phenyl)-benzamide C₃₆H₃₉N₇O₂Mol.Wt.: 601.74 602.22

4-tert-Butyl-N-(2-methyl-3- {8-[4-(N- methylcarbamimidoyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C₃₂H₃₃N₇OMol. Wt.: 531.65 532.23

4-tert-Butyl-N-(3-{8-[4- (N,N′-dimethyl- carbamimidoyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-2-methyl- phenyl)-benzamideC₃₃H₃₅N₇O Mol. Wt.: 545.68 546.19

4-tert-Butyl-N-(3-{8-[4-(4,5- dihydro-1H-imidazol-2-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-2-methyl- phenyl)-benzamideC₃₃H₃₃N₇O Mol. Wt.: 543.66 544.22

4-tert-Butyl-N-{3-[8-(4- carbamimidoyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]- 2-methyl-phenyl}-benzamide C₃₁H₃₁N₇O Mol.Wt.: 517.62 518.06

4-tert-Butyl-N-{3-[8-(4- carbamimidoylmethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl- phenyl}-benzamide C₃₂H₃₃N₇O Mol. Wt.: 531.65532.1

4-tert-Butyl-N-(2-methyl-3- {8-[4-(N- methylcarbamimidoylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C₃₃H₃₅N₇OMol. Wt.: 545.68 546.1

4-tert-Butyl-N-(3-{8-[4- (N,N′-dimethyl- carbamimidoylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-2-methyl- phenyl)-benzamideC₃₄H₃₇N₇O Mol. Wt.: 559.70 560.05

4-tert-Butyl-N-(3-{8-[4-(N,N- dimethyl- carbamimidoylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-2-methyl- phenyl)-benzamideC₃₄H₃₇N₇O Mol. Wt.: 559.70 560.05

EXAMPLE 11

4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile

A mixture of 4-aminobenzonitrile (220 mg; 1.89 mmol) and6,8-dibromo-imidazo[1,2-a]pyrazine (500 mg; 1.81 mmol) is slurried inDMF (1 mL) and heated to 140° C. for 20 minutes. The reaction is allowedto cool, and when the bath reaches 75° C., ethyl acetate (40 mL) isadded and the slurry is stirred to break up large solid lumps into finepowder. The powdered4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile is filtered,washed with diethyl ether (2×50 mL) and dried under vacuum to a fineorange/tan solid (600 mg).

4-[6-(3-Amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrile

A solution of 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile(1.02 g; 3.27 mmol) is slurried in ethylene glycol, dimethyl ether (DME;60 mL) and nitrogen gas bubbled through the reaction for 15 minutes withstirring at rt.

3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-methyl-phenylamine (950 mg;3.63 mmol) and palladium tetrakis(triphenylphosphine) (500 mg; 0.43mmol) are added and nitrogen is bubbled through the reaction slurry foran additional 10 minutes at rt. 20 mL of a 1.0N solution of sodiumcarbonate is added and the biphasic mixture is heated to 95° C. for 16hrs with vigorous stirring under nitrogen. The mixture is partitionedbetween ethyl acetate (100 mL) and water (100 mL) and the water layerextracted with ethyl acetate (2×50 mL). The organic layers are pooled,washed with brine and dried over anhydrous sodium sulfate. The filtrateis then concentrated in vacuo and the crude oil dissolved in a minimumvolume of CH₂Cl₂. Diethyl ether is added and the resulting precipitateis filtered and washed with diethyl ether to provide4-[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrileas a pale tan solid (650 mg).

4-tert-Butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamide

A solution of4-[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrile(380 mg; 1.12 mmol) and diisopropylethylamine (187 mg; 11.45 mmol) inanhydrous THF (25 mL) is stirred under nitrogen at rt. A solution of4-tert-Butyl-benzoyl chloride (230 mg; 1.17 mmol) in 5 mL anhydrous THFis then added dropwise to the stirring reaction solution. After 30minutes, the mixture is partitioned between ethyl acetate (75 mL) andwater (75 mL) and the water layer extracted with ethyl acetate (2×50mL). The organic layers are pooled, washed with brine and dried overanhydrous sodium sulfate. The filtrate is then concentrated in vacuo andthe crude oil dissolved in a minimum volume of CH₂Cl₂. Diethyl ether isadded and the resulting precipitate is filtered and washed with diethylether to provide4-tert-butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamideas a light orange solid (450 mg)

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride

4-tert-Butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamideis slurried in 200 mL ethanol (200 proof) and the reaction cooled to 0°C. in an ice bath. The reaction is then saturated with hydrogen chloridegas and allowed to gradually warm to rt over 16 hrs with stirring. Thesolvent is removed in vacuo and the resulting tan solid4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride (500 mg) is used without furtherpurification.

4-tert-Butyl-N-(2-methyl-3-{8-[4-(N-methylcarbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride (10 mg; 0.26 mmol) is dissolved inmethanol (1 mL) in a glass pressure reaction vessel, and a solution ofmethylamine in THF added (2.0N; 2 mL). The reaction is heated to 50° C.for 2 hr then concentrated in vacuo. The oil is dissolved in 2 mL CH₂Cl₂and diethyl ether (20 mL) is added to precipitate out4-tert-butyl-N-(2-methyl-3-{8-[4-(N-methylcarbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamideas a clean light tan solid (140 mg).

4-tert-Butyl-N-(3-{8-[4-(N,N′-dimethyl-carbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamide

4-tert-Butyl-N-(2-methyl-3-{8-[4-(N-methylcarbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-benzamide(100 mg; 0.19 mmol) is dissolved in methanol (1 mL) in a glass pressurereaction vessel, and a solution of methylamine in THF is added (2.0N; 5mL). The reaction is heated to 60° C. for 16 hr then concentrated invacuo. The resulting oil is dissolved in 2 mL CH₂Cl₂ and diethyl ether(20 mL) is added to precipitate out4-tert-butyl-N-(3-{8-[4-(N,N′-dimethyl-carbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamide(80 mg). Gradient silica flash chromatography using (90:9:1)(CH₂Cl₂:methanol:ammonium hydroxide) as the eluent provides the purematerial as a white solid (60 mg).

Alternatively,4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride (150 mg; 0.26 mmol) is dissolved inmethanol (1 mL) in a glass pressure reaction vessel, and a solution ofmethylamine in THF added (2.0N; 5 mL). The reaction is heated to 60° C.for 16 hr then concentrated in vacuo. The oil is dissolved in 2 mLCH₂Cl₂ and diethyl ether (20 mL) is added to precipitate out4-tert-butyl-N-(3-{8-[4-(N,N′-dimethyl-carbamimidoyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamideas a light tan solid (100 mg). Gradient silica flash chromatographyusing (90:9:1) (CH₂Cl₂:methanol:ammonium hydroxide) as the eluentprovides the pure material as a white solid (50 mg).

4-tert-Butyl-N-(3-{8-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamide

4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidicacid ethyl ester hydrochloride (150 mg; 0.26 mmol) is dissolved inmethanol (5 mL) in a glass pressure reaction vessel, and ethylenediamine(100 mg; excess) is added. The reaction is heated to 60° C. for 16 hrthen concentrated in vacuo. The oil is dissolved in 2 mL CH₂Cl₂ anddiethyl ether (20 mL) is added to precipitate out4-tert-butyl-N-(3-{8-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-2-methyl-phenyl)-benzamideas a light tan solid (100 mg). Gradient silica flash chromatographyusing (90:9:1) (CH₂Cl₂:methanol:ammonium hydroxide) as the eluentprovides the pure material as a white solid (50 mg).

EXAMPLE 12

The following compounds were prepared using procedures similar to thosedescribed in Example 11 above. Structure Name MW M+

4-tert-Butyl-N-(3-{8-[4-(2- imino-2-morpholin-4-yl- ethyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}- 2-methyl-phenyl)-benzamide C₃₆H₃₉N₇O₂Mol.Wt.: 601.74 602.22

4-tert-Butyl-N-(2-methyl-3- {8-[4-(N- methylcarbamimidoyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C₃₂H₃₃N₇OMol. Wt.: 531.65 532.23

4-tert-Butyl-N-(3-{8-[4- (N,N′-dimethyl- carbamimidoyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-2-methyl- phenyl)-benzamideC₃₃H₃₅N₇O Mol. Wt.: 545.68 546.19

4-tert-Butyl-N-(3-{8-[4-(4,5- dihydro-1H-imidazol-2-yl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-2-methyl- phenyl)-benzamideC₃₃H₃₃N₇O Mol. Wt.: 543.66 544.22

4-tert-Butyl-N-{3-[8-(4- carbamimidoyl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]- 2-methyl-phenyl}-benzamide C₃₁H₃₁N₇O Mol.Wt.: 517.62 518.06

4-tert-Butyl-N-{3-[8-(4- carbamimidoylmethyl- phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl- phenyl}-benzamide C₃₂H₃₃N₇O Mol. Wt.: 531.65532.1

4-tert-Butyl-N-(2-methyl-3- {8-[4-(N- methylcarbamimidoylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-phenyl)- benzamide C₃₃H₃₅N₇OMol. Wt.: 545.68 546.1

4-tert-Butyl-N-(3-{8-[4- (N,N′-dimethyl- carbamimidoylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-2-methyl- phenyl)-benzamideC₃₄H₃₇N₇O Mol. Wt.: 559.70 560.05

4-tert-Butyl-N-(3-{8-[4-(N,N- dimethyl- carbamimidoylmethyl)-phenylamino]-imidazo[1,2- a]pyrazin-6-yl}-2-methyl- phenyl)-benzamideC₃₄H₃₇N₇O Mol. Wt.: 559.70 560.05

EXAMPLE 13 Biochemical Btk Assay

A generalized procedure for one standard biochemical Btk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows.

A master mix minus Btk enzyme is prepared containing 1× Cell Signalingkinase buffer (25 mM Tris-HCl, pH 7.5, 5 mM beta-glycerophosphate, 2 mMdithiothreitol, 0.1 mM Na₃VO₄, 10 mM MgCl₂), 0.5 μM Promega PTKBiotinylated peptide substrate 2, and 0.01% BSA. A master mix plus Btkenzyme is prepared containing 1× Cell Signaling kinase buffer, 0.5 μMPTK Biotinylated peptide substrate 2, 0.01% BSA, and 100 ng/well (0.06mU/well) Btk enzyme. Btk enzyme is prepared as follows: full lengthhuman wildtype Btk (accession number NM-000061) with a C-terminal V5 and6×His tag was subcloned into pFastBac vector for making baculoviruscarrying this epitope-tagged Btk. Generation of baculovirus is donebased on Invitrogen's instructions detailed in its published protocol“Bac-toBac Baculovirus Expression Systems” (Cat. Nos. 10359-016 and10608-016). Passage 3 virus is used to infect Sf9 cells to overexpressthe recombinant Btk protein. The Btk protein is then purified tohomogeneity using Ni-NTA column. The purity of the final proteinpreparation is greater than 95% based on the sensitive Sypro-Rubystaining. A solution of 200 μM ATP is prepared in water and adjusted topH7.4 with 1N NaOH. A quantity of 1.25 μL of compounds in 5% DMSO istransferred to a 96-well ½ area Costar polystyrene plate Compounds aretested singly and with an 11-point dose-responsive curve (startingconcentration is 10 μM; 1:2 dilution). A quantity of 18.75 μL of mastermix minus enzyme (as a negative control) and master mix plus enzyme istransferred to appropriate wells in 96-well 12-area costar polystyreneplate. 5 μL of 200 μM ATP is added to that mixture in the 96-well ½ areaCostar polystyrene plate for final ATP concentration of 40 μM. Thereaction is allowed to incubate for 1 hour at room temperature. Thereaction is stopped with Perkin Elmer 1× detection buffer containing 30mM EDTA, 20 nM SA-APC, and 1 nM PT66 Ab. The plate is read usingtime-resolved fluorescence with a Perkin Elmer Envision using excitationfilter 330 nm, emission filter 665 nm, and 2^(nd) emission filter 615nm. IC₅₀ values are subsequently calculated.

EXAMPLE 14 Ramos Cell Btk Assay

Another generalized procedure for a standard cellular Btk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows.

Ramos cells are incubated at a density of 0.5×10⁷ cells/ml in thepresence of test compound for 1 hr at 37° C. Cells are then stimulatedby incubating with 10 μg/ml anti-human IgM F(ab)₂ for 5 minutes at 37°C. Cells are pelleted, lysed, and a protein assay is performed on thecleared lysate. Equal protein amounts of each sample are subject toSDS-PAGE and western blotting with either anti-phosphoBtk(Tyr223)antibody (Cell Signaling Technology #3531) to assess Btkautophosphorylation or an anti-Btk antibody (BD Transduction Labs#611116) to control for total amounts of Btk in each lysate.

EXAMPLE 15 B-Cell Proliferation Assay

A generalized procedure for a standard cellular B-cell proliferationassay that can be used to test compounds disclosed in this applicationis as follows.

B-cells are purified from spleens of 8-16 week old Balb/c mice using aB-cell isolation kit (Miltenyi Biotech, Cat #130-090-862). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic B-cells for 30 min prior to addition of 10 μg/ml of ananti-mouse IgM antibody (Southern Biotechnology Associates Cat #1022-01)in a final volume of 100 μl. Following 24 hr incubation, 1 μCi³H-thymidine is added and plates are incubated an additional 36 hr priorto harvest using the manufacturer's protocol for SPA[³H]thymidine uptakeassay system (Amersham Biosciences #RPNQ 0130). SPA-bead basedfluorescence is counted in a microbeta counter (Wallace Triplex 1450,Perkin Elmer).

EXAMPLE 16 T Cell Proliferation Assay

A generalized procedure for a standard T cell proliferation assay thatcan be used to test compounds disclosed in this application is asfollows.

T cells are purified from spleens of 8-16 week old Balb/c mice using aPan T cell isolation kit (Miltenyi Biotech, Cat #130-090-861). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic T cells in a final volume of 100 μl in flat clear bottomplates precoated for 90 min at 37° C. with 10 μg/ml each of anti-CD3 (BD#553057) and anti-CD28 (BD #553294) antibodies. Following 24 hrincubation, 1 μCi ³H-thymidine is added and plates incubated anadditional 36 hr prior to harvest using the manufacturer's protocol forSPA[³H]thymidine uptake assay system (Amersham Biosciences #RPNQ 0130).SPA-bead based fluorescence was counted in a microbeta counter (WallaceTriplex 1450, Perkin Elmer).

EXAMPLE 17 CD86 Inhibition Assay

A generalized procedure for a standard assay for the inhibition of Bcell activity that can be used to test compounds disclosed in thisapplication is as follows.

Total mouse splenocytes are purified from spleens of 8-16 week oldBalb/c mice by red blood cell lysis (BD Pharmingen #555899). Testingcompounds are diluted to 0.5% DMSO and incubated with 1.25×10⁶splenocytes in a final volume of 200 μl in flat clear bottom plates(Falcon 353072) for 60 min at 37° C. Cells are then stimulated with theaddition of 15 μ[g/ml IgM (Jackson ImmunoResearch 115-006-020), andincubated for 24 hr at 37° C., 5% CO₂. Following the 24 hr incubation,cells are transferred to conical bottom clear 96-well plates andpelleted by centrifugation at 1200×g×5 min. Cells are preblocked byCD16/CD32 (BD Pharmingen #553142), followed by triple staining withCD19-FITC (BD Pharmingen #553785), CD86-PE (BD Pharmingen #553692), and7AAD (BD Pharmingen #51-68981E). Cells are sorted on a BD FACSCaliburand gated on the CD19⁺/7AAD⁻ population. The levels of CD86 surfaceexpression on the gated population is measured versus test compoundconcentration.

EXAMPLE 18 B-ALL Cell Survival Assay

The following is a procedure for a standard B-ALL cell survival studyusing an XTT readout to measure the number of viable cells. This assaycan be used to test compounds disclosed in this application for theirability to inhibit the survival of B-ALL cells in culture. One humanB-cell acute lymphoblastic leukemia line that can be used is SUP-B15, ahuman Pre-B-cell ALL line that is available from the ATCC.

SUP-B15 pre-B-ALL cells are plated in multiple 96-well microtiter platesin 100 μl of Iscove's media+20% FBS at a concentration of 5×10⁵cells/ml. Test compounds are then added with a final conc. of 0.4% DMSO.Cells are incubated at 37° C. with 5% CO₂ for up to 3 days. After 3 dayscells are split 1:3 into fresh 96-well plates containing the testcompound and allowed to grow up to an additional 3 days. After each 24 hperiod, 50 ul of an XTT solution (Roche) is added to one of thereplicate 96-well plates and absorbance readings are taken at 2, 4 and20 hours following manufacturer's directions. The reading taken with anOD for DMSO only treated cells within the linear range of the assay(0.5-1.5) is then taken and the percentage of viable cells in thecompound treated wells are measured versus the DMSO only treated cells.

EXAMPLE 19

The compounds disclosed in the examples above were tested in the Btkbiochemical assay described herein (Example 13) and certain of thosecompounds exhibited an IC₅₀ value less than or equal to 1 micromolar.Certain of those compounds exhibited an IC₅₀ value less than or equal to100 nM. Certain of those compounds exhibited an IC₅₀ value less than orequal to 10 nM.

Some of the compounds disclosed in synthetic Example 2 were tested inthe B-cell proliferation assay (as described in Example 15) andexhibited an IC₅₀ value less than or equal to 10 micromolar. Certain ofthose compounds exhibited an IC₅₀ value less than or equal to 1micromolar. Certain of those compounds exhibited an IC₅₀ value less thanor equal to 500 nM in this assay.

Certain of those compounds did not inhibit T-cell proliferation and hadIC₅₀ values greater than or equal to 5 micromolar when assayed underconditions described herein (as described in Example 16).

Certain compounds disclosed herein exhibited IC₅₀ values for inhibitionof T-cell proliferation that were at least 3-fold, and in some instances5-fold, or even 10-fold greater than the IC₅₀ values of those compoundsfor inhibition of B-cell proliferation.

Some of the compounds disclosed herein were tested in an assay forinhibition of B cell activity (under the conditions described in example17), and exhibited an IC₅₀ value less than or equal to 10 micromolar.Certain of those compounds exhibited an IC₅₀ value less than or equal to1 micromolar. Certain of those compounds exhibited an IC₅₀ value lessthan or equal to 500 nM in this assay.

Some of the compounds disclosed herein were tested in a B-cell leukemiacell survival assay (under the conditions described in example 18), andexhibit an IC₅₀ value less than or equal to 10 micromolar.

Some of the compounds disclosed in disclosed herein exhibited bothbiochemical and cell-based activity. For example, some of the compoundsdisclosed herein exhibited an IC₅₀ value less than or equal to 10micromolar in the Btk biochemical assay described herein (Example 13)and an IC₅₀ so value less than or equal to 10 micromolar in at least oneof the cell-based assays (other than the T-cell assay) described herein(Examples 14, 15, 17 or 18). Certain of those compounds exhibited anIC₅₀ value less than or equal to 1 micromolar in the Btk biochemicalassay described herein (Example 13) and an IC₅₀ value less than or equalto 10 micromolar in at least one of the cell-based assays (other thanthe T-cell assay) described herein (Examples 14, 15, 17 or 18). Certainof those compounds exhibited an IC₅₀ value less than or equal to 0.1micromolar and an IC₅₀ value less than or equal to 10 micromolar in atleast one of the cell-based assays (other than the T-cell assay)described herein (Examples 14, 15, 17 or 18).

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

1. At least one chemical entity comprising a pharmacophore chosen fromradicals of Formula 1

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein * represents a pointof attachment; R₃ is chosen from optionally substituted piperidinyl,tert-butyl and isopropyl; X is chosen from CH and N; and R₁ and R₂ areindependently chosen from hydrogen, lower alkyl, and halo, provided thatat least one of R₁ and R₂ is not hydrogen.
 2. At least one chemicalentity of claim 1 wherein X is CH.
 3. At least one chemical entity ofclaim 1 wherein X is N.
 4. At least one chemical entity comprising apharmacophore chosen from radicals of Formula 1A

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein * represents a pointof attachment; R₄₀ is chosen from hydrogen, hydroxy, lower alkyl,sulfonyl, halo, lower alkoxy, and heteroaryl; and R₁ and R₂ areindependently chosen from hydrogen, lower alkyl, and halo, provided thatat least one of R₁ and R₂ is not hydrogen.
 5. At least one chemicalentity of claim 1 wherein R₁ and R₂ are independently chosen fromhydrogen, methyl, and fluoro.
 6. At least one chemical entity of claim 5wherein R₁ is chosen from methyl and fluoro and R₂ is hydrogen.
 7. Atleast one chemical entity of claim 5 wherein R₂ is chosen from methyland fluoro and R₁ is hydrogen.
 8. At least one chemical entity of claim5 wherein R₁ and R₂ are independently chosen from methyl and fluoro. 9.At least one chemical entity of claim 4 wherein R₄₀ is chosen fromhydrogen and lower alkyl.
 10. At least one chemical entity chosen fromcompounds of Formula 2:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R is chosen fromoptionally substituted cycloalkyl, optionally substituted aryl andoptionally substituted heteroaryl; M is chosen from a covalent bond and—CH═CH—. Q is chosen from

 wherein R₁₀ and R₁₁ are independently chosen from hydrogen, C₁-C₆alkyl, and C₁-C₆ haloalkyl; and R₁₂, R₁₃, R₁₄, and R₁₅ are eachindependently chosen from hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,phenyl, substituted phenyl chosen from mono-, di-, and tri-substitutedphenyl wherein the substituents are independently chosen from hydroxy,nitro, cyano, amino, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₆alkyloxy)C₁-C₆ alkoxy, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy,mono-(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and amino(C₁-C₆ alkyl),heteroaryl, and substituted heteroaryl chosen from mono-, di-, andtri-substituted heteroaryl wherein the substituents are independentlychosen from hydroxy, nitro, cyano, amino, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, (C₁-C₆ alkyloxy)C₁-C₆ alkoxy, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, mono-(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, andamino(C₁-C₆ alkyl); and Z is chosen from optionally substitutedphenylene and optionally substituted pyridylidene; W is an optionallysubstituted heteroaryl group other than imidazo[1,2-A]pyrazine group;and D is a hydrogen bond donor other than hydrogen, provided that thecompound of Formula 2 is not(4-{6-[(4-chloro-benzyl)-methyl-amino]-pyrazin-2-yl}-phenyl)-piperidin-1-yl-methanone.11. At least one chemical entity of claim 10 wherein Z is chosen fromortho-phenylene, meta-phenylene, para-phenylene, ortho-pyridylidene,meta-pyridylidene, and para-pyridylidene, each of which is optionallysubstituted with a group chosen from optionally substituted lower alkyl,optionally substituted lower alkoxy, halo, and hydroxy.
 12. At least onechemical entity of claim 11 wherein Z is chosen from meta-phenylene andmeta-phenylene substituted with a group chosen from optionallysubstituted lower alkyl, optionally substituted lower alkoxy, halo, andhydroxy.
 13. At least one chemical entity of claim 12 wherein Z ischosen from meta-phenylene and meta-phenylene substituted with a groupchosen from lower alkyl and halo.
 14. At least one chemical entity ofclaim 13 wherein Z is chosen from meta-phenylene and meta-phenylenesubstituted with a group chosen from methyl and halo.
 15. At least onechemical entity of claim 10 wherein M is a covalent bond.
 16. At leastone chemical entity of claim 10 wherein M is —CH═CH—.
 17. At least onechemical entity of claim 10 wherein the compound of Formula 2 is chosenfrom compounds of Formula 3:

wherein R₃ is chosen from optionally substituted piperidinyl, tert-butyland isopropyl; X is chosen from CH and N; R₁ and R₂ are independentlychosen from hydrogen, lower alkyl, and halo, provided that at least oneof R₁ and R₂ is not hydrogen.
 18. At least one chemical entity of claim17 wherein X is CH.
 19. At least one chemical entity of claim 17 whereinX is N.
 20. At least one chemical entity of claim 17 wherein R₁ and R₂are independently chosen from hydrogen, methyl, and fluoro.
 21. At leastone chemical entity of claim 20 wherein R₁ is chosen from methyl andfluoro and R₂ is hydrogen.
 22. At least one chemical entity of claim 20wherein R₁ and R₂ are independently chosen from methyl and fluoro. 23.At least one chemical entity of claim 10 wherein W is an optionallysubstituted heteroaryl group that further comprises a hydrogen bondacceptor.
 24. At least one chemical entity of claim 10 wherein

is chosen from

each of which is optionally substituted with one or two groups chosenfrom hydroxy, cyano, halo, optionally substituted lower alkyl, andoptionally substituted lower alkoxy and wherein R₁₆ is chosen fromhydrogen, cyano, optionally substituted cycloalkyl, and optionallysubstituted lower alkyl; R₁₇, R₁₈, R₁₉, R₂₁, R₂₂, and R₂₃ areindependently chosen from hydrogen and optionally substituted loweralkyl; and R₂₀ is chosen from hydrogen, hydroxy, cyano, halo, optionallysubstituted lower alkyl, and optionally substituted lower alkoxy.
 25. Atleast one chemical entity of claim 24 wherein R₁₇, R₁₈, R₁₉, R₂₁, andR₂₂ are independently chosen from hydrogen and lower alkyl
 26. At leastone chemical entity of claim 24 wherein R₂₀ is hydrogen.
 27. At leastone chemical entity of claim 10 wherein

comprises

wherein Y is chosen from N and CR₂₁; and R₁₆, R₂₁, and R₂₂ areindependently chosen from hydrogen and optionally substituted loweralkyl;
 28. At least one chemical entity of claim 10 wherein D is —NHR₉wherein R₉ is chosen from optionally substituted aryl and optionallysubstituted heteroaryl.
 29. At least one chemical entity of claim 10wherein D is —N(H)—B-L-G wherein B is chosen from optionally substitutedphenylene, optionally substituted pyridylidene, optionally substituted2-oxo-1,2-dihydropyridinyl,

wherein indicates the point of attachment to the group -L-G and thebroken bond

 indicates the point of attachment to the amino group; X₁ is chosen fromN and CR₃₁; X₂ is chosen from N and CR₃₁; and X₃ is chosen from N andCR₃₁; and wherein no more than one of X₁, X₂, and X₃ is N, R₃₀ is chosenfrom hydrogen, hydroxy, cyano, halo, optionally substituted lower alkyl,and optionally substituted lower alkoxy; R₃₁ is chosen from hydrogen,hydroxy, cyano, halo, optionally substituted lower alkyl, and optionallysubstituted lower alkoxy; L is chosen from optionally substitutedC₀-C₄alkylene, —O-optionally substituted C₀-C₄alkylene,—(C₀-C₄alkylene)(SO)—, —(C₀-C₄alkylene)(SO₂)—; and—(C₀-C₄alkylene)(C═O)—; and G is chosen from hydrogen, halo, hydroxy,alkoxy, nitro, optionally substituted alkyl, optionally substitutedamino, optionally substituted carbamimidoyl, optionally substitutedheterocycloalkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl.
 30. At leastone chemical entity of claim 29 comprising a compound of Formula 4:


31. At least one chemical entity of claim 29 comprising a compound of


32. At least one chemical entity of claim 30 comprising a compound ofFormula 6:

wherein R₄ is chosen from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, halo, and hydroxy.
 33. At least onechemical entity of claim 31 comprising a compound of Formula 7:

wherein R₄ is chosen from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, halo, and hydroxy.
 34. At least onechemical entity of claim 29 wherein B is chosen from ortho-phenylene,meta-phenylene, para-phenylene,


35. At least one chemical entity of claim 34 wherein B is chosen frompara-phenylene and meta-phenylene.
 36. At least one chemical entity ofclaim 35 wherein B is meta-phenylene.
 37. At least one chemical entityof claim 34 wherein, B is chosen from


38. At least one chemical entity of claim 10 wherein R₁₂, R₁₃, R₁₄, andR₁₅ are each independently chosen from hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, and phenyl.
 39. At least one chemical entity of claim 38wherein R₁₃ is chosen from hydrogen and C₁-C₆ alkyl.
 40. At least onechemical entity of claim 10 wherein R is chosen from phenyl, substitutedphenyl chosen from mono-, di-, and tri-substituted phenyl wherein thesubstituents are independently chosen from hydroxy, lower alkyl,sulfanyl, sulfonyl, optionally substituted amino, lower alkoxy, loweralkyl substituted with one or more halo, lower alkoxy substituted withone or more halo, lower alkyl substituted with hydroxy, lower alkylsubstituted with lower alkoxy, optionally substituted piperidinyl, andheteroaryl, pyridyl, substituted pyridyl chosen from mono-, di-, andtri-substituted pyridyl wherein the substituents are independentlychosen from hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy,optionally substituted piperidinyl, and heteroaryl, pyrimidinyl,substituted pyrimidinyl chosen from mono-, di-, and tri-substitutedpyridyl wherein the substituents are independently chosen from hydroxy,lower alkyl, sulfonyl, halo, lower alkoxy, optionally substitutedpiperidinyl, and heteroaryl, pyrazinyl, substituted pyrazinyl chosenfrom mono-, di-, and tri-substituted pyridyl wherein the substituentsare independently chosen from hydroxy, lower alkyl, sulfonyl, halo,lower alkoxy, optionally substituted piperidinyl, and heteroaryl,pyridazinyl, substituted pyridazinyl chosen from mono-, di-, andtri-substituted pyridyl wherein the substituents are independentlychosen from hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy,optionally substituted piperidinyl, and heteroaryl, oxazol-2-yl,substituted oxazol-2-yl l chosen from mono-, di-, and tri-substitutedoxazol-2-yl wherein the substituents are independently chosen fromhydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, optionallysubstituted piperidinyl, and heteroaryl, 2H-pyrazol-3-yl, substituted2H-pyrazol-3-yl chosen from mono-, di-, and tri-substituted2H-pyrazol-3-yl wherein the substituents are independently chosen fromhydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, optionallysubstituted piperidinyl, and heteroaryl, [1,2,3]thiadiazol-4-yl,substituted [1,2,3]thiadiazol-4-yl chosen from mono-, di-, andtri-substituted [1,2,3]thiadiazol-4-yl wherein the substituents areindependently chosen from hydroxy, lower alkyl, sulfonyl, halo, loweralkoxy, optionally substituted piperidinyl, and heteroaryl,isoxazol-5-yl, substituted isoxazol-5-yl chosen from mono-, di-, andtri-substituted isoxazol-5-yl wherein the substituents are independentlychosen from hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy,optionally substituted piperidinyl, and heteroaryl,4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, substituted4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from mono-, di-, andtri-substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein thesubstituents are independently chosen from hydroxy, lower alkyl,sulfonyl, halo, lower alkoxy, optionally substituted piperidinyl, andheteroaryl, 4,5,6,7-tetrahydrobenzofuran-2-yl, substituted4,5,6,7-tetrahydrobenzofuran-2-yl chosen from mono-, di-, andtri-substituted 4,5,6,7-tetrahydrobenzofuran-2-yl wherein thesubstituents are independently chosen from hydroxy, lower alkyl,sulfonyl, halo, lower alkoxy, optionally substituted piperidinyl, andheteroaryl, 4,5,6,7-tetrahydro-1H-indol-2-yl, substituted4,5,6,7-tetrahydro-1H-indol-2-yl chosen from mono-, di-, andtri-substituted 4,5,6,7-tetrahydro-1H-indol-2-yl wherein thesubstituents are independently chosen from hydroxy, lower alkyl,sulfonyl, halo, lower alkoxy, optionally substituted piperidinyl, andheteroaryl and wherein the amine nitrogen of the indole ring isoptionally substituted with an optionally substituted lower alkyl group,1H-indol-2-yl, substituted 1H-indol-2-yl chosen from mono-, di-, andtri-substituted 1H-indol-2-yl wherein the substituents are independentlychosen from hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy,optionally substituted piperidinyl, and heteroaryl and wherein the aminenitrogen of the indole ring is optionally substituted with an optionallysubstituted lower alkyl group, benzofuran-2-yl, substitutedbenzofuran-2-yl chosen from mono-, di-, and tri-substitutedbenzofuran-2-yl wherein the substituents are independently chosen fromhydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, optionallysubstituted piperidinyl, and heteroaryl, benzo[b]thiophen-2-yl, andsubstituted benzo[b]thiophen-2-yl chosen from mono-, di-, andtri-substituted benzo[b]thiophen-2-yl wherein the substituents areindependently chosen from hydroxy, lower alkyl, sulfonyl, halo, loweralkoxy, optionally substituted piperidinyl, and heteroaryl.
 41. At leastone chemical entity of claim 40 wherein R is chosen from phenyl,substituted phenyl chosen from mono-, di-, and tri-substituted phenylwherein the substituents are independently chosen from hydroxy, loweralkyl, sulfonyl, halo, lower alkoxy, optionally substituted piperidinyl,and heteroaryl, pyridyl, substituted pyridyl chosen from mono-, di-, andtri-substituted pyridyl wherein the substituents are independentlychosen from hydroxy, lower alkyl, sulfonyl, halo, lower alkoxy,optionally substituted piperidinyl, and heteroaryl, oxazol-2-yl,substituted oxazol-2-yl l chosen from mono-, di-, and tri-substitutedoxazol-2-yl wherein the substituents are independently chosen fromhydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, optionallysubstituted piperidinyl, and heteroaryl, 2H-pyrazol-3-yl, substituted2H-pyrazol-3-yl chosen from mono-, di-, and tri-substituted2H-pyrazol-3-yl wherein the substituents are independently chosen fromhydroxy, lower alkyl, sulfonyl, halo, lower alkoxy, optionallysubstituted piperidinyl, and heteroaryl,4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, substituted4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from mono-, di-, andtri-substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein thesubstituents are independently chosen from hydroxy, lower alkyl,sulfonyl, halo, lower alkoxy, optionally substituted piperidinyl, andheteroaryl, [1,2,3]thiadiazol-4-yl, substituted [1,2,3]thiadiazol-4-ylchosen from mono-, di-, and tri-substituted [1,2,3]thiadiazol-4-ylwherein the substituents are independently chosen from hydroxy, loweralkyl, sulfonyl, halo, lower alkoxy, optionally substituted piperidinyl,and heteroaryl, isoxazol-5-yl, and substituted isoxazol-5-yl chosen frommono-, di-, and tri-substituted isoxazol-5-yl wherein the substituentsare independently chosen from hydroxy, lower alkyl, sulfonyl, halo,lower alkoxy, optionally substituted piperidinyl, and heteroaryl.
 42. Atleast one chemical entity of claim 41 wherein R is chosen from4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl and substituted4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from mono-, di-, andtri-substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein thesubstituents are independently chosen from hydroxy, lower alkyl,sulfonyl, halo, lower alkoxy, and heteroaryl.
 43. At least one chemicalentity of claim 42 wherein R is chosen from4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl and substituted4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl chosen from mono-, di-, andtri-substituted 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl wherein thesubstituents is lower alkyl.
 44. At least one chemical entity of claim43 wherein R is substituted phenyl chosen from mono-, di-, andtri-substituted phenyl wherein the substituents are independently chosenfrom hydroxy, lower alkyl, sulfanyl, sulfonyl, optionally substitutedamino, lower alkoxy, lower alkyl substituted with one or more halo,lower alkoxy substituted with one or more halo, lower alkyl substitutedwith hydroxy, lower alkyl substituted with lower alkoxy, optionallysubstituted piperidinyl, and heteroaryl.
 45. At least one chemicalentity of claim 44 wherein R is substituted phenyl chosen from mono-,di-, and tri-substituted phenyl wherein the substituents areindependently chosen from hydroxy, lower alkyl, sulfonyl, halo, loweralkoxy, optionally substituted piperidinyl, and heteroaryl.
 46. At leastone chemical entity of claim 45 wherein R is 4-lower alkyl-phenyl-. 47.At least one chemical entity of claim 46 wherein R is4-tert-butyl-phenyl.
 48. At least one chemical entity of claim 46wherein R is 4-iso-propyl-phenyl.
 49. At least one chemical entity ofclaim 45 wherein R is phenyl substituted with an optionally substitutedpiperidinyl.
 50. At least one chemical entity of claim 32 comprising acompound of Formula 8:

and wherein X is chosen from N and CH; U is chosen from N and CR₄₁; R₄₁is chosen from hydrogen, halo, optionally substituted lower alkyl,optionally substituted lower alkoxy, hydroxy, nitro, cyano, sulfhydryl,sulfanyl, sulfinyl, sulfonyl, carboxy, aminocarbonyl, and optionallysubstituted amino; and R₅ is chosen from hydrogen, hydroxy, lower alkyl,sulfonyl, optionally substituted amino, lower alkoxy, lower alkylsubstituted with one or more halo, lower alkoxy substituted with one ormore halo, lower alkyl substituted with hydroxy, optionally substitutedheterocycloalkyl, and optionally substituted heteroaryl.
 51. At leastone chemical entity of claim 33 comprising a compound of Formula 9:

and wherein X is chosen from N and CH; U is chosen from N and CR₄₁; R₄₁is chosen from hydrogen, halo, optionally substituted lower alkyl,optionally substituted lower alkoxy, hydroxy, nitro, cyano, sulfhydryl,sulfanyl, sulfinyl, sulfonyl, carboxy, aminocarbonyl, and optionallysubstituted amino; R₅ is chosen from hydrogen, halo, hydroxy, loweralkyl, sulfanyl, sulfonyl, optionally substituted amino, lower alkoxy,cycloalkyl, optionally substituted heterocycloalkyl, lower alkylsubstituted with hydroxy, lower alkyl substituted with one or more halo,lower alkoxy substituted with one or more halo, lower alkyl substitutedwith hydroxy, and optionally substituted heteroaryl.
 52. At least onechemical entity of claim 29 wherein L is chosen from optionallysubstituted C₀-C₄alkylene, —O-optionally substituted C₀-C₄alkylene,—(C₀-C₄alkylene)(SO₂)—; and —(C₀-C₄alkylene)(C═O)—.
 53. At least onechemical entity of claim 52 wherein L is chosen from a covalent bond,—(C═O)—, —CH₂—, —CH₂(C═O)—, —SO₂—, and —CH(CH₃)(C═O)—.
 54. At least onechemical entity of claim 53 wherein L is chosen from —(C═O)—, —CH₂—,—CH₂(C═O)—, —SO₂— and —CH(CH₃)(C═O)—.
 55. At least one chemical entityof claim 50 comprising a compound of Formula 10:

wherein f is chosen from 0, 1 and
 2. 56. At least one chemical entity ofclaim 55 comprising a compound of Formula 11:


57. At least one chemical entity of claim 51 comprising a compound ofFormula 12:

wherein f is chosen from 0, 1 and
 2. 58. At least one chemical entity ofclaim 57 comprising a compound of Formula 13:


59. At least one chemical entity of claim 58 wherein the groupG-C(O)—(CH₂)_(f)— is attached to the 3 position of the ring.
 60. Atleast one chemical entity of claim 58 wherein the groupG-C(O)—(CH₂)_(f)— is attached to the 4 position of the ring.
 61. Atleast one chemical entity of claim 29 wherein G is chosen from hydrogen,hydroxy, —NR₇R₈ wherein R₇ and R₈ are independently chosen fromhydrogen, optionally substituted acyl, and optionally substituted(C₁-C₆)alkyl; or wherein R₇ and R₈, together with the nitrogen to whichthey are bound, form an optionally substituted 5- to 7-membered nitrogencontaining heterocycloalkyl which optionally further includes one or twoadditional heteroatoms chosen from N, O, and S; optionally substituted5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl, lower alkoxy, and1H-tetrazol-5-yl.
 62. At least one chemical entity of claim 61 wherein Gis chosen from hydrogen, hydroxy, N-methylethanolamino, optionallysubstituted morpholin-4-yl, optionally substituted piperazin-1-yl, andoptionally substituted homopiperazin-1-yl.
 63. At least one chemicalentity of claim 62 wherein G is chosen from hydrogen, morpholin-4-yl,4-acyl-piperazin-1-yl, 4-lower alkyl-piperazin-1-yl,3-oxo-piperazin-1-yl, homopiperazin-1-yl, and 4-loweralkyl-homopiperazin-1-yl.
 64. At least one chemical entity of claim 55comprising a compound of Formula 14:

wherein R₇ and R₈ are independently chosen from hydrogen and optionallysubstituted (C₁-C₆)alkyl; or R₇ and R₈, together with the nitrogen towhich they are bound, form an optionally substituted 5- to 7-memberednitrogen-containing heterocycloalkyl which optionally further includesone or two additional heteroatoms chosen from N, O, and S.
 65. At leastone chemical entity of claim 57 comprising a compound of Formula 15:

wherein R₇ and R₈ are independently chosen from hydrogen and optionallysubstituted (C₁-C₆)alkyl; or R₇ and R₈, together with the nitrogen towhich they are bound, form an optionally substituted 5- to 7-memberednitrogen containing heterocycloalkyl which optionally further includesone or two additional heteroatoms chosen from N, O, and S.
 66. At leastone chemical entity of claim 64 wherein R₇ and R₈, together with thenitrogen to which they are bound, form a 5- to 7-memberednitrogen-containing heterocycloalkyl chosen from optionally substitutedmorpholin-4-yl and optionally substituted piperazin-1-yl ring.
 67. Atleast one chemical entity of claim 66 wherein R₇ and R₈, together withthe nitrogen to which they are bound, form a 5- to 7-memberednitrogen-containing heterocycloalkyl chosen from morpholin-4-yl,4-acyl-piperazin-1-yl, and 4-lower alkyl-piperazin-1-yl.
 68. At leastone chemical entity of claim 29 comprising a compound of Formula 16:

wherein X is chosen from N and CH; R₅ is chosen from hydrogen, hydroxy,lower alkyl, sulfonyl, optionally substituted amino, lower alkoxy, loweralkyl substituted with one or more halo, lower alkoxy substituted withone or more halo, lower alkyl substituted with hydroxy, optionallysubstituted heterocycloalkyl, and optionally substituted heteroaryl; R₄is chosen from hydrogen, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, halo, and hydroxy; R₁₆ is chosen fromhydrogen, cyano, optionally substituted cycloalkyl, and optionallysubstituted lower alkyl; and R₂₂ is chosen from hydrogen and optionallysubstituted lower alkyl.
 69. At least one chemical entity of claim 29comprising a compound of Formula 17:

wherein X is chosen from N and CH; R₅ is chosen from hydrogen, hydroxy,lower alkyl, sulfonyl, optionally substituted amino, lower alkoxy, loweralkyl substituted with one or more halo, lower alkoxy substituted withone or more halo, lower alkyl substituted with hydroxy, optionallysubstituted heterocycloalkyl, and optionally substituted heteroaryl; R₄is chosen from hydrogen, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, halo, and hydroxy; R₁₆ is chosen fromhydrogen, cyano, optionally substituted cycloalkyl, and optionallysubstituted lower alkyl; and R₂₂ is chosen from hydrogen and optionallysubstituted lower alkyl.
 70. At least one chemical entity of claim 29comprising a compound of Formula 18:

wherein X is chosen from N and CH; R₅ is chosen from hydrogen, hydroxy,lower alkyl, sulfonyl, optionally substituted amino, lower alkoxy, loweralkyl substituted with one or more halo, lower alkoxy substituted withone or more halo, lower alkyl substituted with hydroxy, optionallysubstituted heterocycloalkyl, and optionally substituted heteroaryl; R₄is chosen from hydrogen, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, halo, and hydroxy; R₁₆ is chosen fromhydrogen, cyano, optionally substituted cycloalkyl, and optionallysubstituted lower alkyl; and R₂₂ is chosen from hydrogen and optionallysubstituted lower alkyl.
 71. At least one chemical entity of claim 29comprising a compound of Formula 19:

wherein X is chosen from N and CH; R₅ is chosen from hydrogen, hydroxy,lower alkyl, sulfonyl, optionally substituted amino, lower alkoxy, loweralkyl substituted with one or more halo, lower alkoxy substituted withone or more halo, lower alkyl substituted with hydroxy, optionallysubstituted heterocycloalkyl, and optionally substituted heteroaryl; R₄is chosen from hydrogen, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, halo, and hydroxy; R₁₆ is chosen fromhydrogen, cyano, optionally substituted cycloalkyl, and optionallysubstituted lower alkyl; and R₂₂ is chosen from hydrogen and optionallysubstituted lower alkyl.
 72. At least one chemical entity of claim 68wherein L is a covalent bond and G is hydrogen.
 73. At least onechemical entity of claim 55 wherein f is
 0. 74. At least one chemicalentity of claim 50 wherein U is CR₄₁.
 75. At least one chemical entityof claim 50 wherein R₅ is chosen from hydrogen, optionally substitutedpiperidinyl, and lower alkyl.
 76. At least one chemical entity of claim75 wherein R₅ is chosen from hydrogen, optionally substitutedpiperidinyl, iso-propyl, and tert-butyl.
 77. At least one chemicalentity of claim 75 wherein R₅ is tert-butyl.
 78. At least one chemicalentity of claim 30 wherein R₂₂ is chosen from hydrogen and methyl. 79.At least one chemical entity of claim 78 wherein R₂₂ is hydrogen.
 80. Atleast one chemical entity of claim 10, wherein the at least one chemicalentity exhibits an IC₅₀ of 10 micromolar or less in an in vitrobiochemical assay of Btk activity.
 81. At least one chemical entity ofclaim 80, wherein the at least one chemical entity exhibits an IC₅₀ of 1micromolar or less in an in vitro biochemical assay of Btk activity. 82.At least one chemical entity of claim 81, wherein the at least onechemical entity exhibits an IC₅₀ of 0.1 micromolar or less in an invitro biochemical assay of Btk activity.
 83. At least one chemicalentity of claim 10 wherein the at least one chemical entity exhibits anIC₅₀ of 10 micromolar or less in an assay for inhibition of B-cellactivity.
 84. At least one chemical entity of claim 83 wherein the atleast one chemical entity exhibits an IC₅₀ of 1 micromolar or less in anassay for inhibition of B-cell activity.
 85. At least one chemicalentity of claim 84 wherein the at least one chemical entity exhibits anIC₅₀ of 500 nanomolar or less in an assay for inhibition of B-cellactivity.
 86. At least one chemical entity of claim 10 wherein the atleast one chemical entity exhibits an IC₅₀ value in an assay forinhibition of T-cell proliferation that is at least 3-fold greater thanan IC₅₀ value exhibited by the at least one chemical entity exhibits inan assay for inhibition of B-cell proliferation.
 87. At least onechemical entity of claim 86, wherein the at least one chemical entityexhibits an IC₅₀ value in an assay for inhibition of T-cellproliferation that is at least 5-fold greater than an IC₅₀ value thatthe at least one chemical entity exhibits in an assay for inhibition ofB-cell proliferation.
 88. At least one chemical entity of claim 87,wherein the at least one chemical entity exhibits an IC₅₀ value in anassay for inhibition of T-cell proliferation that is at least 10-foldgreater than an IC₅₀ value that the at least one chemical entityexhibits in an assay for inhibition of B-cell proliferation.
 89. Atleast one chemical entity of claim 10 wherein the at least one chemicalentity exhibits an IC₅₀ of 10 micromolar or less in a B-ALL cellsurvival assay.
 90. At least one chemical entity of claim 10 wherein thecompound of Formula 1 is chosen from4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(morpholine-4-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;4-{5-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-benzoicacid;4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(N-methylethanolamine-2-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyrazin-3-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(morpholine-4-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;4-{5-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-benzoicacid;4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-(N-methylethanolamine-2-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyrazin-3-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{1-methyl-5-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid ethyl ester;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{4-methyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-ethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-tert-Butyl-N-(3-{4-ethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{4-ethyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-ethyl-6-[4-(N-methylethanolamine-2-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{4-ethyl-6-[4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-fluoro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4,5-dimethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-fluoro-benzoicacid;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(1H-indazol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(1H-indazol-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[3-fluoro-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-methanesulfonylaminocarbonyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{4-methyl-6-[4-(3-aminopropyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1l14-thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1l6-thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1H-tetrazol-5-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid ethyl ester;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{4-methyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-ethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-tert-Butyl-N-(3-{4-ethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{4-ethyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-ethyl-6-[4-(N-methylethanolamine-2-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{4-ethyl-6-[4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-fluoro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4,5-dimethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-fluoro-benzoicacid;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(1H-indazol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(1H-indazol-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[3-fluoro-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(5-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-methanesulfonylaminocarbonyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{4-methyl-6-[4-(3-aminopropyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(1H-imidazol-2-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-methyl-5-[4-methyl-5-oxo-6-(4-sulfamoyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1H-tetrazol-5-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-phenyl]-4,5-dimethyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-tert-Butyl-N-(3-{3,4-dimethyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[3-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N,N-bis-(2-hydroxyethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N,N-bis-(2-hydroxyethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1H-tetrazol-5-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzenesulfinicacid morpholin-4-yl ester;N-{3-[6-(1H-Benzoimidazol-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(2-cyano-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-[3-[6-(6-hydroxy-pyridin-3-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-methyl-N-(cyanomethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(6-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-pyridin-2-yl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(2-methoxyethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(2-dimethylaminoethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-oxazol-2-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-6-(4-oxazol-2-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(4-imidazol-1-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-{2-fluoro-3-[6-(4-imidazol-1-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N,N-bis-(2-methoxyethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-(3-{6-[4-(4-Acetyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[4-(4-Acetyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-Bromo-N-(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholine-4-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-(1-Hydroxy-1-methyl-ethyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-thiomorpholin-4-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(4-imidazol-1-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-Bromo-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-fluoro-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(4-oxo-piperidine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxymethyl-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(2-hydroxymethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;5-tert-Butyl-thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-6-(4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(N-(2-(2-hydroxy-ethoxy)-ethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{2-fluoro-3-[6-(4-imidazol-1-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-([1,4]oxazepane-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-(4-methyl-6-[4-(N-(2,3-dihydroxy-propyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-thiomorpholin-4-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-hydroxymethyl-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(2-hydroxymethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-thiomorpholin-4-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-cyclohexanecarboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-tert-Butyl-N-(3-{4-ethyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-Dimethylamino-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(4-oxo-4H-pyridin-1-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-Isopropyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-(1-Hydroxy-1-methyl-ethyl)-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-5-oxo-6-(4-pyrrolidin-1-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-ylmethyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-N-(2-Methoxy-ethyl)-N-methylaminocarbonyl-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2,4-difluoro-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-methoxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-methyl-N-ethylaminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyrrolidine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3-phenyl-acrylamide;N-(2-Fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-3-(3-fluoro-phenyl)-acrylamide;Benzo[b]thiophene-2-carboxylic acid(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;Benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;5-Bromo-thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;5-Bromo-thiophene-2-carboxylic acid(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;N-(2-Fluoro-3-(4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-methylsulfanyl-benzamide;N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-methylsulfanyl-benzamide;4-Ethylsulfanyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;Benzofuran-2-carboxylic acid(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4,5-Dibromo-thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[6-(1-oxo-1λ⁴-thiomorpholin-4-yl)-pyridin-3-ylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2,6-difluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-Cyclopropyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(3-fluoro-4-thiomorpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[3-fluoro-4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl)-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;4-tert-Butyl-N-(3-{6-[4-(4-methoxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-methanesulfonyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-methanesulfonyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-cyclohexanecarboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(ethyl-methyl-amino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(ethyl-methyl-amino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(2-morpholin-4-yl-pyridin-4-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;Benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;N-(3-{6-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-{3-[6-(4-hydroxymethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-(6-[4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-piperidin-1-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-pyridin-4-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-fluoro-3-[4-methyl-6-(4-methylaminomethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(3-ethyl-1-methyl-ureidomethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(3-hydroxymethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(3-hydroxy-pyrrolidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-pyridin-3-yl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-[2-fluoro-3-(6-[4-[(methanesulfonyl-methyl-amino)-methyl]-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxy-pyridin-3-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;1-(4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-piperidine-4-carboxylicacid amide;4-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-N-methyl-benzamide;N-(3-{6-[4-(4-Acetyl-[1,4]diazepan-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-ethyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;1-(4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-piperidine-3-carboxylicacid amide;1-(4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-pyrrolidine-2-carboxylicacid amide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(pyridin-4-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamino]-4-ethyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1-oxy-pyridin-3-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1-oxy-pyridin-4-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide4-tert-Butyl-N-(3-{6-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-carbamimidoylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{4-cyclopropyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(3-dimethylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(pyridin-4-ylmethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(pyridin-3-ylmethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;6-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxy-pyridin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(1-ethyl-2-oxo-1,2-dihydro-pyridin-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{4-cyano-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(piperidin-4-yl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(3-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;5,6,7,8-Tetrahydro-naphthalene-2-carboxylic acid(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(1-ethyl-piperidin-4-yl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-hydroxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(4-methanesulfonyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;N-{3-[6-(3-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperidin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(3-hydroxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(2-pyridin-4-yl-ethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-methyl-thiazol-4-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;6-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;N-(2-Methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;6-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl)-nicotinamide;4-tert-Butyl-N-(2-methyl-3-(4-methyl-6-[4-(N-(3-amino-phenyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-(3-{6-[4-(4-Amino-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-(3-{6-[4-(1-ethyl-piperidin-4-yloxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;N-{3-[6-(Benzothiazol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;N-(3-{6-[4-(2-Amino-pyridin-4-ylmethoxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-{3-[6-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(2-fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-morpholin-4-yl-acetyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;5-tert-Butyl-pyridine-2-carboxylic acid(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ4-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;N-(2-Fluoro-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;4-tert-Butyl-N-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;6-tert-Butyl-N-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-nicotinamide;N-{3-[6-(3-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-6-tert-butyl-nicotinamide;3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;N-{3-[6-(2-Amino-pyridin-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N,N-bis-(2-methoxy-ethyl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;5-tert-Butyl-pyridine-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;5-tert-Butyl-pyridine-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-Iodo-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-{3-[6-(3-Benzylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(tetrahydro-pyran-4-yl)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide;N-(2-Methyl-3-(4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-pyrrolidin-1-yl-benzamide;Tetrahydro-furan-2-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;4-tert-Butyl-N-(3-{6-[3-(cyclohexanecarbonyl-amino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;N-{3-[6-(3-Amino-4-fluoro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;5,6-Dihydro-4H-cyclopenta[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[1-(2-morpholin-4-yl-ethyl)-2-oxo-1,2-dihydro-pyridin-4-ylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-(2-Methyl-3-{4-methyl-6-[4-(1-methyl-piperidin-4-yloxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;6-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;6-tert-Butyl-N-[3-(6-{4-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-nicotinamide;4-(6-{3-[(6-tert-Butyl-pyridine-3-carbonyl)-amino]-2-methyl-phenyl)-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoicacid; Benzo[b]thiophene-5-carboxylic acid(2-methyl-3-[4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[3-(pyridin-3-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl)-phenyl)-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[3-(pyridin-3-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;4,4-Dimethyl-chroman-7-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;6-tert-Butyl-N-(3-(6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;6-tert-Butyl-N-(2-fluoro-3-{6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[3-(pyridin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[3-(pyridin-4-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;6-tert-Butyl-N-(3-{6-[4-(2-hydroxymethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;6-tert-Butyl-N-(2-fluoro-3-{6-[4-(2-hydroxymethyl-morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;6-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-[1,4]diazepane-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;6-tert-Butyl-N-(3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;6-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;N-{3-[6-(4-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;N-(3-{6-[4-(4-Amino-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-6-tert-butyl-nicotinamide;4-(6-{3-[(6-tert-Butyl-pyridine-3-carbonyl)-amino]-2-fluoro-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoicacid;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-3-ylmethoxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-[4-methyl-5-oxo-6-[4-(pyridin-3-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-3-yloxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;6-tert-Butyl-N-[2-fluoro-3-(6-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl]-nicotinamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(N-(hydroxy)aminocarbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-{3-[6-(3-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-piperidin-1-yl-benzamide;6-tert-Butyl-N-[3-(6-{4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-nicotinamide;6-tert-Butyl-N-(3-{6-[4-(cyanomethyl-methyl-carbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;N-(3-{6-[4-(4-Ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;6-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;N-{2-Methyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-4-piperidin-1-yl-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(N-(1-amino-ethylidene))-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(3-cyclopropylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(3-piperidin-1-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-[3-(6-{3-[(cyanomethyl-methyl-amino)-methyl]-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl}-benzamide;1-(3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzyl)-piperidine-4-carboxylicacid amide;4-tert-Butyl-N-{3-[6-(3-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-[3-(6-{3-[(2-hydroxy-ethylamino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-(3-{6-[3-(4-hydroxy-piperidin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-(6-[3-(2-hydroxymethyl-morpholin-4-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;Tetrahydro-furan-2-carboxylic acid(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;Tetrahydro-furan-3-carboxylic acid(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino]-phenyl)-amide;3,4,5,6-Tetrahydro-2H-[1,3′]bipyridinyl-6′-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;6-tert-Butyl-N-(2-fluoro-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;N-(3-{6-[4-(1,1-Dioxo-1l6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;6-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1l6-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-nicotinamide;2-tert-Butyl-pyrimidine-5-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;6-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(pyridin-3-ylmethoxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;N-(3-{6-[4-(4-Amino-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-6-tert-butyl-nicotinamide;6-tert-Butyl-N-(2-fluoro-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;5-tert-Butyl-pyrazine-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;6-tert-Butyl-N-(2-fluoro-3-{6-[4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;N-(2-Methyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;N-(3-{6-[4-(4-Ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;6-tert-Butyl-N-(2-fluoro-3-(4-methyl-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-nicotinamide;6-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-nicotinamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(4-oxo-piperidin-1-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-(3-{6-[4-(3-Amino-propylcarbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-6-tert-butyl-nicotinamide;N-(3-{6-[4-(4-Hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide6-tert-Butyl-N-(3-{6-[4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;4-Azepan-1-yl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;5-tert-Butyl-pyridine-2-carboxylic acid(2-fluoro-3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;N-{3-[5-(3-Amino-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;Tetrahydro-furan-2-carboxylic acid(3-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino}-phenyl)-amide;4-tert-Butyl-N-{3-[1,4-dimethyl-5-(4-morpholin-4-yl-phenylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{5-[4-(1,1-dioxo-1l6-thiomorpholin-4-yl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide;6-tert-Butyl-N-(3-{6-[4-(carbamoylmethyl-methyl-carbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;6-tert-Butyl-N-{3-[6-(4-hydroxycarbamoyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-nicotinamide;5-tert-Butyl-pyridine-2-carboxylic acid(3-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-(3-{6-[4-(4-Amino-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4-{6-[3-(4-(1-piperidinyl)-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzohydroxamicacid; 5-tert-Butyl-pyridine-2-carboxylic acid(3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl)-amide;5-tert-Butyl-pyrazine-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;5-tert-Butyl-pyridine-2-carboxylic acid(3-{6-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-(4-methyl-piperidin-1-yl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;5-tert-Butyl-pyridine-2-carboxylic acid(3-{6-[4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-(2-Methyl-3-{4-methyl-5-oxo-6-[4-(3-oxo-piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;4-(1-Piperidinyl)-N-(3-{4-methyl-6-[4-(2-hydroxyethyl-methyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-[4-methyl-5-oxo-6-(1H-pyrazol-3-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;N-(3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-isonicotinamide;5-tert-Butyl-pyrazine-2-carboxylic acid(3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;Tetrahydro-furan-2-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-fluoro-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;5-tert-Butyl-pyridine-2-carboxylic acid(3-{6-[4-(carbamoylmethyl-methyl-carbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[4-(carbamoylmethyl-methyl-carbamoyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-(3-methyl-piperidin-1-yl)-benzamide;N-{3-[6-(3-Acetylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;Tetrahydro-furan-3-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;Thiazole-4-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;(3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-carbamicacid ethyl ester;4-tert-Butyl-N-(3-{6-[3-(2-methoxy-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;5-tert-Butyl-pyrimidine-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-(Isopropyl-methyl-amino)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(2-methyl-3-{6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;N-[2-Methyl-3-(4-methyl-5-oxo-6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-4-piperidin-1-yl-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;N-[3-(6-{4-[4-(2-Hydroxy-ethyl)-piperazine-1-carbonyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-piperidin-1-yl-benzamide;1-(4-{4-Methyl-6-[2-methyl-3-(4-piperidin-1-yl-benzoylamino)-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-piperidine-4-carboxylicacid amide; 5-tert-Butyl-pyrazine-2-carboxylic acid(3-{6-[4-(4-amino-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide;4-tert-Butyl-N-[2-fluoro-3-(4-methyl-6-{3-[2-(4-methyl-piperazin-1-yl)-acetylamino]-phenylamino}-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide;N-{3-[6-(3-Amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-fluoro-phenyl}-4-tert-butyl-benzamide;N-{3-[6-(3-Amino-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;5-tert-Butyl-pyridine-2-carboxylic acid(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperazine-1-carbonyl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;Tetrahydro-furan-2-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;Tetrahydro-furan-2-carboxylic acid[3-(6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-phenyl]-amide;Tetrahydro-furan-2-carboxylic acid(5-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-fluoro-phenyl)-amide;Acetic acid3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenylester;N-(2-Methyl-3-{6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-piperidin-1-yl-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(morpholin-2-ylmethoxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;6-tert-Butyl-pyridazine-3-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-Imidazol-1-yl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[3-(3-methoxy-propionylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;Furan-2-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;6-tert-Butyl-N-(3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-nicotinamide;4-tert-Butyl-N-[3-(6-{4-[2-(4-ethyl-piperazin-1-yl)-ethoxy]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;(3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-carbamicacid tetrahydro-furan-3-yl ester; Tetrahydro-furan-2-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;Tetrahydro-furan-2-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;N-{3-[6-(5-Amino-pyridin-3-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-{3-[6-(1H-indol-5-ylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;Pyrrolidine-2-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;4-tert-Butyl-N-(3-{6-[3-(2-hydroxy-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-[3-(6-cyclopropylamino-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-[3-(6-hydroxy-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-(3-{6-[3-(2-ethoxy-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;N-{3-[6-(3-Amino-4-methyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[3-(2-hydroxy-2-methyl-propionylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;Tetrahydro-pyran-4-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(4-thiomorpholin-4-ylmethyl-phenylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-(4-Hydroxy-piperidin-1-yl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl)-phenyl}-benzamide;N-{3-[6-(3-Amino-4-chloro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-(2-methyl-piperidin-1-yl)-benzamide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;4-tert-Butyl-N-{3-[6-(3-dimethylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperidin-4-ylmethoxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-[3-(6-{4-[(2-hydroxy-ethylamino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;(3-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-carbamicacid phenyl ester;4-tert-Butyl-N-{3-[6-(4-cyclopropylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-[3-(6-{4-[(carbamoylmethyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-(4-Methoxymethoxy-piperidin-1-yl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-(3-{6-[3-(2-Amino-acetylamino)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;Azetidine-2-carboxylic acid(3-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-amide;Tetrahydro-furan-2-carboxylic acid(5-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methyl-phenyl)-amide;4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-4-methyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;1-Methyl-3-[4-(morpholine-4-carbonyl)-phenylamino]-5-(2-phenyl-benzooxazol-7-yl)-1H-pyrazin-2-one;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(1-methyl-piperidin-2-ylmethoxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;5-[2-(4-Methoxy-phenyl)-benzooxazol-7-yl]-1-methyl-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazin-2-one;4-tert-Butyl-N-{3-[6-(1H-indol-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;N-{3-[6-(3-Aminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-(3-{6-[4-(1-ethyl-piperidin-4-ylmethoxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1-pyridin-4-ylmethyl-1H-indol-6-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-Furan-2-yl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-(2-Methoxy-1,1-dimethyl-ethyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-4-methyl-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[4-(4-hydroxy-4-methyl-piperidin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;6-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid{3-[6-(3-amino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-hydroxy-benzoicacid;4-tert-Butyl-N-(2-methyl-3-[4-methyl-6-[4-(morpholine-4-carbonyl)-3-nitro-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl)-benzamide;5-Ethyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-Azetidin-1-yl-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-3-methoxy-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methoxy-benzoicacid; 1,4,4-Trimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4-(1-Methoxy-1-methyl-ethyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-(2,2-Dimethyl-propionyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-(3-{6-[3-methoxy-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methoxy-N-(3-methoxy-propyl)-benzamide;N-{3-[6-(3-Acryloylamino-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-{3-[6-(1H-indol-4-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-[3-(6-{4-[(2-methoxy-ethylamino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-{3-[6-(4-ethylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(4-diethylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-[3-(6-{4-[(isopropyl-methyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[4-(2-methyl-piperidin-1-ylmethyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[2-(tetrahydro-pyran-4-ylamino)-ethyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide;5-Amino-2-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-cyclopropyl-benzamide;5-Amino-benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;2-Amino-N-{3-[6-(benzothiazol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-piperidin-1-yl-benzamide;4-tert-Butyl-N-[3-(6-{2-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-4-ylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-(3-{6-[3-methoxy-4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-hydroxy-ethyl)-2-methoxy-N-methyl-benzamide;4-tert-Butyl-N-(3-{6-[3-methoxy-4-(piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;N-{3-[6-(3-Amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;N-{3-[6-(4-Amino-2-piperidin-1-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;(4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzylamino)-aceticacid;4-tert-Butyl-N-[3-(6-{4-[(cyclopropylmethyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;N-{3-[6-(3-Amino-4-thiomorpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-5-oxo-6-[4-(piperidin-3-ylmethoxy)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-(3-{6-[3-Amino-4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-5-oxo-6-(1,2,3,4-tetrahydro-isoquinolin-6-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-[3-(6-{4-[2-(4-ethyl-piperazin-1-yl)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-[3-(6-{4-[2-(2-hydroxy-ethylamino)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-{3-[6-(4-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-(3-{6-[4-(2-diethylamino-ethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-hydroxy-ethyl)-N-methyl-benzamide;4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-(3-Methoxymethoxy-piperidin-1-yl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-hydroxymethyl-3-methoxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(1H-indol-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;N-(3-{6-[3-Amino-4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-dimethylamino-ethyl)-benzamide;4-tert-Butyl-N-{2-methyl-3-[6-(4-morpholin-4-yl-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-morpholin-4-yl-3-nitro-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;N-{3-[6-(3-Amino-4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-diethylamino-ethyl)-benzamide;4-tert-Butyl-N-(3-{4-ethyl-6-[4-(phenyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-(3-{4-ethyl-6-[4-(2-methyl-phenyl-carbamoyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-benzamide;4-tert-Butyl-N-{3-[6-(4-cyclopropylaminomethyl-3-methoxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(4-cyclopropylaminomethyl-3-methoxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;4-tert-Butyl-N-{3-[6-(3-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;N-(3-{6-[3-Amino-4-(1-oxo-1λ⁴-thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4-(1-Methyl-cyclobutyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-{3-[6-(4-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-[3-(6-{3-[2-(2-hydroxy-ethylamino)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[3-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;4-tert-Butyl-N-[3-(6-{3-[2-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;4-tert-Butyl-N-[3-(6-{3-[2-(4-ethyl-piperazin-1-yl)-ethyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-benzamide;N-{3-[6-(3-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-tert-Butyl-N-{3-[6-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;N-(3-{6-[4-(4-Aminomethyl-4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoicacid;5-(3-Amino-2-methyl-phenyl)-1-methyl-3-(4-morpholin-4-yl-3-nitro-phenylamino)-1H-pyrazin-2-one;5-tert-Butyl-pyridine-2-carboxylic acid{3-[6-(3-amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid{3-[6-(3-amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;N-{3-[6-(3-Amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-piperidin-1-yl-benzamide;N-(2-Methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-4-methylsulfanyl-benzamide;N-{3-[6-(3-Amino-4-cyclopropylaminomethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-(3-{6-[3-Amino-4-(thiomorpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-pyridin-3-yl-benzamide;N-(5-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-N-(2-methoxy-ethyl)-N-methyl-benzamide;Octahydro-isoquinoline-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-6-tert-butyl-nicotinamide;N-{3-[6-(2-Amino-indan-5-ylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-4-tert-butyl-benzamide;N-{3-[6-(3-Amino-4-methoxy-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(4-ethyl-piperazin-1-ylmethyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;1-(2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-piperidine-4-carboxylicacid amide;N-{3-[6-(3-Amino-4-morpholin-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-fluoro-phenyl}-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(4-ethyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[4-(4-Aminomethyl-4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[4-(1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-pentafluoroethyl-benzamide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid{2-methyl-3-[4-methyl-6-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-amide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-amide;N-{3-[6-(3-Amino-4-[1,4]oxazepan-4-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-[3-(6-{3-Amino-4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;4-tert-Butyl-N-{3-[6-(3-methoxy-4-morpholin-4-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;N-(3-{6-[3-Amino-4-(4-hydroxy-4-methyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(2-morpholin-4-yl-ethoxy)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-[3-(6-{3-Amino-4-[(2-methoxy-ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methyl-benzoicacid methyl ester;4-{6-[3-(4-tert-Butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-2-methyl-benzoicacid; 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-fluoro-phenyl)-amide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(3-methyl-4-morpholin-4-yl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4-methyl-5-oxo-6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-amide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-[1,4]oxazepan-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid{3-[6-(4-hydroxymethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid[3-(6-{4-[(carbamoylmethyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;1-(2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-4-hydroxy-pyridinium;N-[3-(6-{3-Amino-4-[(2-hydroxy-ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;N-(3-{6-[3-Amino-4-(4-methyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;5,6,7,8-Tetrahydro-naphthalene-2-carboxylic acid(2-methyl-3-{4-methyl-5-oxo-6-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino]-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-amide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4-methyl-5-oxo-6-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-amide;4-tert-Butyl-N-{2-methyl-3-[4-methyl-6-(4-[1,4]oxazepan-4-ylmethyl-phenylamino)-5-oxo-4,5-dihydro-pyrazin-2-yl]-phenyl}-benzamide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid{3-[6-(4-hydroxymethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-amide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid[3-(6-{4-[(carbamoylmethyl-amino)-methyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide;5-Methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;1-(2-Amino-4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-4-hydroxy-pyridinium;N-[3-(6-{3-Amino-4-[(2-hydroxy-ethyl)-methyl-amino]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-piperidin-1-yl-benzamide;N-(3-{6-[3-Amino-4-(4-methyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-(3-{6-[3-Amino-4-(3-hydroxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(3-hydroxy-pyrrolidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-{3-[6-(3-Amino-4-piperidin-1-yl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide;4-(2-Hydroxy-1,1-dimethyl-ethyl)-N-(2-methyl-3-{4-methyl-6-[4-(morpholine-4-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;1-[2-Amino-4-(4-methyl-6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoyl]-piperidine-4-carboxylicacid amide; 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(3-hydroxy-pyrrolidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(4-ethyl-piperazine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(3-hydroxy-piperidine-1-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;N-(3-{6-[3-Amino-4-(4-methyl-[1,4]diazepan-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(4-hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;1-[2-Amino-4-(4-methyl-6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-phenyl]-piperidine-4-carboxylicacid amide; 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid(3-{6-[3-amino-4-(2-hydroxymethyl-morpholin-4-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-amide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid[3-{6-(3-amino-4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[3-nitro-4-(pyridin-3-yloxy)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide;N-[3-(6-{3-Amino-4-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide;4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid{2-methyl-3-[4-methyl-5-oxo-6-(pyridin-3-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-amide;4-tert-Butyl-N-{3-[6-(3-fluoro-4-morpholin-4-ylmethyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide;N-(3-{6-[3-Amino-4-(4-methoxy-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(4-cyano-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;1-[2-Amino-4-(4-methyl-6-{2-methyl-3-[(4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-phenyl]-piperidine-3-carboxylicacid amide;N-(3-{6-[3-Amino-4-(3-hydroxymethyl-piperidin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;N-(3-{6-[3-Amino-4-(3-methyl-piperazin-1-yl)-phenylamino]-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-2-methyl-phenyl)-4-tert-butyl-benzamide;and 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid{2-methyl-3-[4-methyl-5-oxo-6-(pyridin-4-ylamino)-4,5-dihydro-pyrazin-2-yl]-phenyl}-amide.91. A pharmaceutical composition, comprising at least one chemicalentity of claim 10, together with at least one pharmaceuticallyacceptable vehicle chosen from carriers, adjuvants, and excipients. 92.A pharmaceutical composition of claim 91, wherein the composition isformulated in a form chosen from injectable fluids, aerosols, creams,gels, tablets, pills, capsules, syrups, ophthalmic solutions, andtransdermal patches.
 93. A packaged pharmaceutical composition,comprising a pharmaceutical composition of claim 91; and instructionsfor using the composition to treat a patient suffering from a diseaseresponsive to inhibition of Btk activity.
 94. The packagedpharmaceutical composition of claim 93 wherein the disease responsive toinhibition of Btk activity is cancer.
 95. The packaged pharmaceuticalcomposition of claim 93 wherein the disease responsive to inhibition ofBtk activity is chosen from allergic disorders, autoimmune diseases,inflammatory diseases, and acute inflammatory reactions.
 96. A methodfor treating a patient having a disease responsive to inhibition of Btkactivity, comprising administering to the patient an effective amount ofat least one chemical entity of claim
 10. 97. The method of claim 96wherein the patient is a human.
 98. The method of claim 96 wherein thepatient is chosen from cats and dogs.
 99. The method of claim 96 whereinthe disease responsive to inhibition of Btk activity is cancer.
 100. Themethod of claim 99 wherein the disease responsive to inhibition of Btkactivity is B-cell lymphoma and leukemia.
 101. The method of claim 96wherein an effective amount of said at least one chemical entity isadministered by a method chosen from intravenously, intramuscularly, andparenterally.
 102. The method of claim 96 wherein an effective amount ofsaid at least one chemical entity is administered orally.
 103. A methodfor treating a patient having a disease chosen from cancer, autoimmunediseases, inflammatory diseases, acute inflammatory reactions, andallergic disorders comprising administering to the patient an effectiveamount of at least one chemical entity of claim
 10. 104. The method ofclaim 103 wherein the patient is a human.
 105. The method of claim 103wherein the patient is chosen from cats and dogs.
 106. The method ofclaim 103 wherein an effective amount of said at least one chemicalentity is administered by a method chosen from intravenously,intramuscularly, and parenterally.
 107. The method of claim 103 whereinan effective amount of said at least one chemical entity is administeredorally.
 108. A method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a patient undergoingchemotherapy with a chemotherapeutic agent an amount of at least onechemical entity of claim 10, sufficient to increase the sensitivity ofcancer cells to the chemotherapeutic agent.
 109. A method of reducingmedication error and enhancing therapeutic compliance of a patient beingtreated for a disease responsive to inhibition of Btk activity, themethod comprising providing a packaged pharmaceutical preparation ofclaim 93 wherein the instructions additionally include contraindicationand adverse reaction information pertaining to the packagedpharmaceutical composition.
 110. A method for inhibiting ATP hydrolysis,the method comprising contacting cells expressing Btk with at least onechemical entity of claim 10 in an amount sufficient to detectablydecrease the level of ATP hydrolysis in vitro.
 111. The method of claim110 wherein the cells are present in a mammal.
 112. The method of claim111 wherein the mammal is a human.
 113. The method of claim 111 whereinthe mammal is chosen from cats and dogs.
 114. A method for determiningthe presence of Btk in a sample, comprising contacting the sample withat least one chemical entity of claim 10 under conditions that permitdetection of Btk activity, detecting a level of Btk activity in thesample, and therefrom determining the presence or absence of Btk in thesample.
 115. A method for inhibiting B-cell activity comprisingcontacting cells expressing Btk with at least one chemical entity, ofclaim 10, in an amount sufficient to detectably decrease B-cell activityin vitro.